AbstractPharmaceutically active compounds (PhACs) are emerging contaminants that have been widely detected in water bodies in the last decades, with ecological effects toward aquatic biota that have not been fully elucidated. Most studies concerning their toxicity to microalgae have only considered short‐term individual PhAC exposure, rather than combined exposure to several compounds for longer time periods. In this study, we investigated the effects of albendazole (ABZ) (anthelmintic) and carbamazepine (antiepileptic), alone and in combination with caffeine, on the growth and production of chlorophyll‐a of the microalgae Raphidocelis subcapitata, during 16 days of exposure. ABZ alone had a more significant effect than carbamazepine alone on the growth rate and maximum cell density of the microalgae (p < .05; analysis of variance). These results were probably related to the effect of ABZ in inhibiting enzyme complexes and cell membrane proteins related to adenosine triphosphate synthesis, which is important for cell growth. The presence of caffeine lowered the toxicities of ABZ and carbamazepine to the microalgae, probably due to its antioxidant properties, positively affecting chlorophyll‐a production, growth rate, and maximum cell density. Thus, caffeine had an antagonistic interaction with the studied PhACs. The results reinforce the importance of ecotoxicological assays that compare individual and combined PhAC exposure conditions. Our findings highlighted that caffeine can be a relevant factor influencing such assays, considering its widespread occurrence in impacted water bodies.