Rapid changes in salinity, as with other environmental stressors, can have detrimental effects on fish and may trigger increased susceptibility to disease. However, the precise mechanisms of these effects are not well understood. We examined the effects of sudden increases or decreases in salinity on teleost immune function using Nile tilapia, Oreochromis niloticus (L.), as the fish model in a battery of bioassays of increasing immune system specificity. Two different salinity experiments were performed: one of increasing salinity (0 to 5, 10 and 20 g L−1) and one of decreasing salinity (20 to 15, 10 and 5 g L−1). Histopathology of anterior kidney, gills, gonads, intestines and liver of exposed fish was performed, but no remarkable lesions were found that were attributable to the salinity treatment regimes. The spleen was removed from each fish for analysis of cytokine expression, and peripheral blood was used for haematology, cortisol and phagocytosis assays. In the increasing salinity experiments, no significant changes were observed in any immune system assays. However, in the decreasing salinity experiments, lymphopenia, neutrophilia and monocytosis were observed in the peripheral blood without modification of the packed cell volume, plasma protein or plasma cortisol levels. Phagocytosis was increased in response to decreases in salinity from 20 g L−1 to 15 g L−1, 10 g L−1 and 5 g L−1, whereas phagocytic index was not significantly altered. Transforming growth factor-β (TGF-β) transcription increased during the same decreases in salinity. However, the TGF-β value at 5 g L−1 was less than those in the 15 and 10 g L−1 salinity treatments. Interleukin-1β (IL-1β) transcription did not significantly respond to either salinity regime. In total, acute salinity changes appeared to trigger reactive dysregulation of the immune response in tilapia, a situation which, when combined with additional co-occurring stressors such as sudden changes in temperature and/or dissolved oxygen, could make fish more susceptible to infectious diseases. Accordingly, these findings may help to explain how sudden environmental changes may initiate disease outbreaks and lead to critical declines in cultured or wild fish populations.