The Santa Ana Freeway is one of the principal freeways in Southern California, connecting Los Angeles and its southeastern suburbs including the freeway's namesake, the city of Santa Ana. The freeway begins at its junction with the San Diego Freeway (Interstate 405, I-405), called the El Toro Y, in Irvine, signed as I-5. From there, it generally goes southeast to northwest to the East Los Angeles Interchange, where it takes the designation of U.S. Route 101 (US 101). It then proceeds 2.95 miles (4.75 km) northwest to the Four Level Interchange (also known as the Bill Keene Memorial Interchange) in downtown Los Angeles. Formerly, the entirety of the route was marked as US 101 until the 1964 highway renumbering, which truncated US 101 to the East Los Angeles Interchange and designated the rest of the freeway as I-5.

North of the East Los Angeles Interchange complex, I-5 follows the Golden State Freeway. South of the El Toro Y, I-5 takes on the San Diego Freeway name from I-405.

The infamously busy intersection of the Santa Ana, Garden Grove, and Orange freeways in southwestern Orange is nicknamed the Orange Crush.

The freeway is officially defined as Routes 101 and 5 from Route 110 (Four Level Interchange) to Route 405.

The Santa Ana Freeway is a bypass of the original state highway from Los Angeles to Santa Ana, which passed through Whittier and mostly became SR 72 in the 1964 renumbering. Southeast of Santa Ana, this earlier highway, added to the state highway system in 1910 as Route 2, generally followed the present freeway from Tustin past East Irvine to El Toro. This route was marked as part of US 101 in 1928.

In 1933, the state legislature added a number of routes to the state highway system, including two that later formed parts of the Santa Ana Freeway. Route 166 began at the new Route 172 (now SR 60), at the corner of Indiana and Third Streets, and headed south on Indiana Street and east and southeast on Mines Avenue (Olympic Boulevard) and Anaheim-Telegraph Road (now Telegraph Road) to Route 171 (now SR 39) at the intersection with Los Nietos Road near Santa Fe Springs. Route 174 began at Route 60 (then signed Alternate U. S. 101 now SR 1) in what now is known as Westchester and followed Manchester Avenue and Firestone Boulevard (then under construction alongside the Southern Pacific Railroad's Santa Ana Branch) to Route 2 (then Los Angeles Street, now Anaheim Boulevard) in southern Anaheim. A second piece began further southeast on Route 2, where it turned east on Chapman Avenue, and followed the shorter Santa Ana Boulevard diagonally to Route 2 (Main Street) in northern Santa Ana. In 1934, Route 166, except on Indiana Street, was marked as part of Sign Route 6 (which continued along Route 171 to Buena Park), and the entire length of Route 174 became Sign Route 10. (SR 6 was renumbered to SR 26 in 1937, when US 6 entered California; SR 10 was soon truncated to Anaheim Boulevard, as US 101 had moved from Route 2 to the shorter Route 174 in Santa Ana.)

A U.S. Route 101 Bypass was created by 1941, beginning at the intersection of Routes 166 (Indiana Street, soon moved to Downey Road^{[citation needed]}) and 2 (US 101 along Whittier Boulevard), and following Routes 166 and 174 to Route 2 (US 101) in Anaheim. The connection between Routes 166 and 174 was made via Route 168 (Rosemead Boulevard, then and now SR 19). This resulted in SR 10 being truncated further, to the intersection of Firestone and Rosemead Boulevards, though SR 26 continued to extend east on Routes 166 and 171 to Buena Park.

A freeway connecting downtown Los Angeles with Orange County was planned by 1939, and was included in A Transit Program for the Los Angeles Metropolitan Area, published that year by the Metropolitan Transportation Engineering Board. To allow for its construction by the state, the definition of Route 166 was modified in 1941, changing the southeast end to Route 174 near Norwalk; at the same time, the northernmost piece was changed from Indiana Street to Downey Road.