From May 3 to May 11, 2003, a prolonged and destructive series of tornado outbreaks affected much of the Great Plains and Eastern United States. Most of the severe activity was concentrated between May 4 and May 10, which saw more tornadoes than any other week-long span in recorded history; 335 tornadoes occurred during this period, concentrated in the Ozarks and central Mississippi River Valley. Additional tornadoes were produced by the same storm systems from May 3 to May 11, producing 363 tornadoes overall, of which 62 were significant. Six of the tornadoes were rated F4, and of these four occurred on May 4, the most prolific day of the tornado outbreak sequence; these were the outbreak's strongest tornadoes. Damage caused by the severe weather and associated flooding amounted to US$4.1 billion (US$5.8 billion in 2016), making it the costliest U.S. tornado outbreak of the 2000s. A total of 50 deaths and 713 injuries were caused by the severe weather, with a majority caused by tornadoes; the deadliest tornado was an F4 that struck Madison and Henderson counties in Tennessee, killing 11. In 2023, tornado expert Thomas P. Grazulis created the outbreak intensity score (OIS) as a way to rank various tornado outbreaks. The tornado outbreak sequence of May 2003 received an OIS of 232, making it the fifth worst tornado outbreak in recorded history.

During the first half of May 2003, atmospheric conditions across the Central and Southeastern United States proved exceptionally favorable for widespread severe weather. Idealized patterns for large tornado outbreaks occurred each day from May 3 to 11, resulting in a prolonged and extensive series of outbreaks. Warm, moist air flowed northward from the Gulf of Mexico across the Central United States and reached as far north as Missouri. This created an anomalously large warm sector–the airmass behind a warm front and ahead of a dry line–for thunderstorms to develop within. The unusually far-reaching nature of this airmass resulted in the greatest tornadic activity occurring outside the climatological maximum area for tornadoes in May. Atop the northward surface winds, the upper-level jet stream blew almost perpendicular, creating strong wind shear across Kansas, Missouri, Oklahoma, and Tennessee. Multiple shortwave troughs initiated tornadic events throughout the outbreak. As severe weather shifted east across the country, another trough would cross from the Pacific to the Central United States and reignite activity. The cause of these successive troughs is unknown, but they proved a key factor in the prolonged nature of the outbreak. Throughout this period, no cold fronts propagated south from Canada; the lack of these allowed the atmosphere to continually destabilize and fuel further thunderstorms. The pattern finally ceased on May 11–12 with the active pattern shifting to New England the formation of a ridge over the Rocky Mountains.

Throughout the nine-day outbreak, 363 tornadoes touched down across the United States. Of these, 62 reached at least F2-intensity, while 6 reached F4. The most prolific and violent day of the outbreak was May 4; 79 tornadoes touched down, of which 4 reached F4-intensity. Between May 4 and May 10, 335 tornadoes developed across 26 states, setting a record for the most tornadoes ever documented over the course of a week. At least one significant tornado was reported daily across nine consecutive days, with at least a dozen tornadoes total occurring daily over the same timeframe. Due to the temporal expanse of the event, it was classified as a tornado outbreak sequence—a "continuous or near-continuous sequence of tornado outbreak days"—with only three historical events of comparable longevity and severity according to data compiled by Thomas P. Grazulis. May 2003 ultimately became the most active month for tornadoes in recorded history until it was later surpassed by April 2011. In total, the widespread severe weather event caused an estimated $4.1 billion (2003; $5.8 billion 2019 CPI-adjusted) in damage and 41 deaths alongside 642 injuries.

On April 30, meteorologists at the Storm Prediction Center (SPC) noted the likelihood of a major tornado outbreak across a large area of the Central and Eastern United States for the period of May 2–6. Ahead of the most active day, the SPC issued a rare high-risk outlook for severe weather across eastern Oklahoma, eastern Kansas, western Missouri, and northwestern Arkansas. A total of 127 severe weather watches and 4,050 warnings (2,960 severe thunderstorm and 1,090 tornado) were issued from May 4. Of the watches, 25 were classified as Particularly Dangerous Situations, a type of watch reserved for the most life-threatening events. The issuance of such watches resulted in an average lead-time of 2 hours and 3 minutes for fatal tornadoes. Seven of the eight fatal tornadoes occurred within a high-risk outlook area, with the eighth just outside in a moderate-risk area. An average of 12 watches were issued each day; May 6, 8, and 10 saw more than 20 each. Watches were continuously in effect from 16:40 UTC on May 4 through 12:00 UTC on May 9. May 6 saw the greatest number of advisories with a record 921 warnings. The SPC and the National Weather Services offices in Kansas City, Springfield, Memphis, Paducah, and Oklahoma City received a letter of praise signed by 11 members of the United States House Committee on Science, Space, and Technology commending their high-quality service during the event. Furthermore, the SPC webpage received an average of 5.6 million views per day during the outbreak.

On the morning of May 3, the SPC predicted that a trough would intensify over the eastern U.S., resulting in a wide and expanding area of increased wind shear and atmospheric instability across the southeastern U.S. Strong southerly winds in the lower levels of the troposphere over the central Great Plains were also expected to advect warm and moist air into the Great Plains. These factors were forecast to provide a conducive environment for severe weather across much of the U.S.; the SPC would delineate moderate risks for severe weather in parts of the central Great Plains, Red River region, and southeastern U.S. over the course of the day, with a lesser but nonetheless extant expectation of severe weather extending outwards from the focal areas. The first severe watch on May 3 was a severe thunderstorm watch issued for parts of the Gulf Coast at 14:14 UTC (9:14 a.m. CDT) in connection with a mesoscale convective system that had been tracking southeast over eastern Mississippi and western Alabama during the morning. The outflow from this complex of storms was expected to also trigger additional severe thunderstorms within an environment favorable for large hail and strong winds near the Gulf Coast. However, the SPC noted that the day's most conducive environment of severe weather—conditional on the development of storms—lay farther west over the southern Great Plains along a decaying warm front and a dry line.

The SPC issued a tornado watch at 18:15 UTC (1:15 p.m. CDT) for parts of Arkansas, Louisiana, Oklahoma, and Texas. Although an atmospheric sounding from Fort Worth, Texas, showed the presence of a capping inversion that prevented storm development, sufficient daytime heating could initiate storms that could develop in the otherwise favorable conditions for severe weather in place. By 21:00 UTC (4:00 p.m. CDT), a line of towering cumulus and cumulonimbus clouds emerged along the dry line east of Lubbock, Texas, resulting in a focused threat area for large hail, strong wind gusts, and isolated tornadoes in southwestern Oklahoma and northwestern Texas. Concurrently, decreasing air pressures, steepening lapse rates, and increasing moisture resulted in another conducive area for severe weather over the central Great Plains and along the eastern periphery of the Rocky Mountains. A tornado watch was issued for northeastern Colorado and northwestern Nebraska in response to this emergent favorability for severe weather at 22:10 UTC (5:10 p.m. CDT).

By 01:00 UTC (8:00 p.m. CDT), severe thunderstorms were active over the Oklahoma/Texas region and the Dakotas/Nebraska area. The final tornado watch of the day was issued for western Oklahoma and northwestern Texas at 01:05 UTC (8:05 p.m. CDT) and expired at 07:00 UTC (2:00 a.m. CDT). Tornadoes were reported in Mississippi, Nebraska, South Dakota, and Texas throughout the day; there were 18 tornado reports, though only 14 tornadoes were confirmed. Although the SPC received its first tornado report at 21:17 UTC (4:17 p.m. CDT) from Meade County, South Dakota, the first confirmed tornado was an F0 tornado that touched down at 21:41 UTC (4:41 p.m. CDT) near Minatare in Scotts Bluff County, Nebraska. The strongest tornado of the day was an F2 tornado that touched down near Lake Stamford in Texas at around 00:10 UTC (7:00 p.m. CDT). The tornado originated from an isolated supercell thunderstorm that had developed along the dry line in northwestern Texas; the same thunderstorm produced at least three other tornadoes during its two-hour traversal of Haskell County, Texas.

May 4 was the most active day of the tornado outbreak sequence: the SPC received 94 tornado reports, though surveys and reanalyses confirmed 79 tornadoes. At the time, this was the second largest number of tornadoes in the U.S. in a single day on record, behind only April 3, 1974. The 38 tornadoes confirmed in Missouri was the highest single-day total for the state and were more numerous than any previous month on record. The day's severe weather was largely driven by a powerful mid-tropospheric disturbance moving northeast across the central and northern Great Plains in tandem with an unusually strong area of low pressure over northeastern Kansas. These weather features were also positioned beneath a negatively-tilted trough and an anomalously robust portion of a jet stream. A cold front and dry line were located south and southwest of the low-pressure area while a warm front spanned from the system southeast to the Tennessee Valley.