The term fish kill, also known as fish die-off, refers to a localized mass die-off of fish populations in a body of water, which may also be associated with more generalized mortality of aquatic life. The most common cause is anoxia in the water, which in turn may be due to factors such as drought, harmful algal bloom, overpopulation, or a sustained increase in water temperature. Infectious diseases and parasites can also lead to fish kill. Toxicity is a real but far less common cause of fish kill, and is often associated with man-made water pollution.

Fish kills are often the first visible signs of environmental stress and are usually investigated as a matter of urgency by environmental agencies to determine the cause of the kill. Many fish species have a relatively low tolerance of variations in environmental conditions and their death is often a potent indicator of problems in their environment that may be affecting other animals and plants and may have a direct impact on other uses of the water such as for drinking water production. Pollution events may affect fish species and fish age classes in different ways. If it is a cold-related fish kill, juvenile fish or species that are not cold-tolerant may be selectively affected. If toxicity is the cause, species are more generally affected and the event may include amphibians and shellfish as well. A reduction in dissolved oxygen may affect larger specimens more than smaller fish as these may be able to access oxygen richer water at the surface, at least for a short time.

Fish kills may result from a variety of causes. Of known causes, fish kills are most frequently caused by pollution from agricultural runoff or biotoxins. Ecological hypoxia (oxygen depletion) is one of the most common natural causes of fish kills. The suffocating event may be brought on by factors such as algae blooms, droughts, high temperatures and thermal pollution. Fish kills may also occur due to the presence of disease, agricultural runoff, sewage discharges, oil or hazardous waste spills, hydraulic fracturing wastewater, sea-quakes, inappropriate re-stocking of fish, poaching with chemicals, underwater explosions, and other catastrophic events that upset a normally stable aquatic population. Because of the difficulty and lack of standard protocol to investigate fish kills, many fish kill cases are designated as having an unknown cause.

Oxygen enters the water through diffusion. The amount of oxygen that can be dissolved in water depends on the atmospheric pressure, the water temperature and whether the water is salty. For example, at 20 °C (68 °F) and one atmosphere of pressure, a maximum of 8 mg/L of oxygen can dissolve in sea water (35 mg/L salinity) while a maximum of 9 mg/L of oxygen can dissolve in fresh water. The amount of oxygen that can be dissolved in the water decreases by about 1 mg/L for each 10 °C increase in water temperature above 20 °C.

Many cold water fish that live in clean cold waters become stressed when oxygen concentrations fall below 8 mg/L while warm water fish generally need at least 5 ppm (5 mg/L) of dissolved oxygen. Fish can endure short periods of reduced oxygen. Depleted oxygen levels are the most common cause of fish kills. Oxygen levels normally fluctuate even over the course of a day and are affected by weather, temperature, the amount of sunlight available, and the amount of living and dead plant and animal matter in the water. In temperate zones oxygen levels in eutrophic rivers in summertime can exhibit very large diurnal fluctuations with many hours of oxygen supersaturation during daylight followed by oxygen depletion at night. Associated with these photosynthetic rhythms there is a matching pH rhythm as bicarbonate ion is metabolised by plant cells. This can lead to pH stress even when oxygen levels are high.

Additional dissolved organic loads are the most common cause of oxygen depletion and such organic loads may come from sewage, farm waste, tip/landfill leachate and many other sources.

Fish are subject to various viruses, bacteria and fungi in addition to parasites such as protozoans, flukes and worms, or crustaceans. These are naturally occurring in many bodies of water, and fish that are stressed for other reasons, such as spawning or suboptimal water quality, are more susceptible. Signs of disease include sores, missing scales or lack of slime, strange growths or visible parasites, and abnormal behavior–lazy, erratic, gasping at the water surface or floating head, tail or belly up.

For example, since 2004 fish kills have been observed in the Shenandoah River basin in the spring, from the time water temperatures are in the 50s (°F) until they reach the mid-70s. So far, investigators suspect certain bacteria, along with environmental and contaminant factors that may cause immune suppression.