When exposed to anoxia insects rapidly go into a hypometabolic coma from which they can recover when exposed to normoxia again. However, prolonged anoxic bouts eventually lead to death in most insects, although some species are surprisingly tolerant. Anoxia challenges ATP, ion, pH and water homeostasis, but it is not clear how fast and to what degree each of these parameters are disrupted during anoxia, nor how quickly they recover. Further, it has not been investigated which disruptions are the primary source of the tissue damage that ultimately causes death. Here we show, in the migratory locust (Locusta migratoria), that prolonged anoxic exposures are associated with increased recovery time, decreased survival, rapidly disrupted ATP and pH homeostasis and a more slowly disruption of ion ([K+] and [Na+] ) and water balance. Locusts could not fully recover after 4 hours of anoxia at 30 °C, and at this point hemolymph [K+] and [Na+] was elevated 5-fold and decreased 2-fold, respectively, muscle [ATP] was decreased to ≤3% of normoxic values, hemolymph pH had dropped 0.8 units from 7.3 to 6.5, and hemolymph water content was halved. These physiological changes are associated with marked tissue damage in vivo and we show that the isolated and combined effects of hyperkalemia, acidosis and anoxia can all cause muscle tissue damage in vitro to equally large degrees. When locusts were returned to normoxia after a moderate (2 hour) exposure of anoxia, ATP recovered rapidly (15 min) and this was quickly followed by recovery of ion balance (30 min), while pH recovery took 2-24 hours. Recovery of [K+] and [Na+] coincided with the animals exiting the comatose state, but recovery to an upright position took∼90 min and was not related to any of the physiological parameters examined.