Aquatic species are continuously exposed to pharmaceuticals and changeable water conditions simultaneously, which can induce changes in the toxicity of pollutants. Cyanobacterium are an organism for which less ecotoxicological tests have been performed compared to green algae. In this study, we decided to check how selected non-steroidal anti-inflammatory drugs (NSAID) affect the grow of Synechocystis salina, picocyanobacterium isolated from the Baltic Sea, with salinity as potential modulator of toxicity. S. salina was exposed to diclofenac (DCF), ibuprofen (IBF) and naproxen (NPX) (nominal 100 mg L−1) in BG11 medium and sea salt supplemented BG11 medium (38 PSU) over 96 h in continuous light at 23 °C. No acute toxicity was found in both tested salinity levels. The comparable grow rate in exposed culture compared to control culture over 4 days indicate lack of stress for several generations which need to be overcome with substantial energy consumption. S. salina was found to be halotolerant and can be species for ecotoxicology test where salinity in an additional stressor. Furthermore, resistant of S. salina to target NSAIDs provide a competitive advantage over other phytoplankton species. Display omitted •S. salina is opportunistic to high concentrations of NSAIDs.•The high salinity (38 PSU) caused salt shock, but cyanobacteria cells adapted.•The NSAIDs were stable in test conditions, and they did not bioaccumulate.•The 38 PSU had a minor effect on the toxicity of NSAIDs toward S. salina.