In Vietnam, the production of striped catfish Pangasianodon hypophthalmus S. reached more than 1.2 millions of tons in 2014 and is mainly gathered in the Mekong Delta (South Vietnam). A survey was carried out during the dry season 2013 (March–April) and rainy season 2014 (July–August) in 12 fish farms of the lower (Tra Vinh Province) and higher (Can Tho Province) Mekong River Delta. This study allowed drawing up current key osmoregulatory and innate immune parameters of striped catfish in aquaculture depending on the geographical location, particularly the proximity to the River Mekong Estuary and the seasonal surface runoff. In the dry season, plasma osmolality was positively correlated with salinity. Gill Na+K+ ATPase dropped in the rainy season, while kidney Na+K+ ATPase remained stable. Abundance of immune blood cells, especially thrombocytes and monocytes, tended to increase in farms located in tidal area. Production of reactive oxygen species in the spleen, kidney lysozyme activity and plasma complement activity did not vary whatever the season or the proximity to the estuary. Plasma lysozyme activity was 50-fold higher than in kidney and increased in the rainy season as well as in tidal sites. Kidney complement activity decreased in the dry season, especially in tidal sites. In conclusion, regarding key osmoregulatory and immune factors, striped catfish farms located in the Mekong Delta may be affected by seasonal and regional salinity and runoff fluctuations.