The physiological tolerances of non-native fishes is an integral component of assessing potential invasive risk. Salinity and temperature are environmental variables that limit the spread of many non-native fishes. We hypothesised that combinations of temperature and salinity will interact to affect survival, growth, and reproduction of Nile tilapia, Oreochromis niloticus, introduced into Mississippi, USA. Tilapia withstood acute transfer from fresh water up to a salinity of 20 and survived gradual transfer up to 60 at typical summertime (30°C) temperatures. However, cold temperature (14°C) reduced survival of fish in saline waters ≥10 and increased the incidence of disease in freshwater controls. Although fish were able to equilibrate to saline waters in warm temperatures, reproductive parameters were reduced at salinities ≥30. These integrated responses suggest that Nile tilapia can invade coastal areas beyond their point of introduction. However, successful invasion is subject to two caveats: (1) wintertime survival depends on finding thermal refugia, and (2) reproduction is hampered in regions where salinities are ≥30. These data are vital to predicting the invasion of non-native fishes into coastal watersheds. This is particularly important given the predicted changes in coastal landscapes due to global climate change and sea-level rise.