<p>Owing to the critical role of phytoplankton as primary producers in aquatic ecosystems, the presence of pharmaceuticals and other micropollutants affects their community structure and ability to perform critical environmental roles. However, most studies have considered the effects of individual pharmaceuticals on phytoplankton, whereas in nature, several pharmaceuticals are simultaneously detected, making investigations of their combined effects critical for the conservation of aquatic diversity and health. This study investigated the combined effects of Diclofenac, Ibuprofen, and Paracetamol on phytoplankton communities using a mesocosm approach. Controlled outdoor mesocosm tanks were used to examine the impact of Diclofenac (DIC), Ibuprofen (IBU) and Paracetamol (PA) at 27.16, 20.89, and 6.92&#xa0;µg L⁻¹ for a single exposure, and DIC + IBU = 22.39&#xa0;µg L⁻¹, DIC + PA = 25.11&#xa0;µg L⁻¹, IBU + PA = 26.30&#xa0;µg L⁻¹, DIC + IBU + PA = 1.87&#xa0;µg L⁻¹for mixed exposure. All three drugs and their combinations adversely affected phytoplankton biomass and community structure with increasing exposure time. However, the combination of all three drugs resulted in more significant adverse effects on physiological and community structure parameters. <i>Pediastrum</i><i>, </i><i>Euastrum</i>, and <i>Micractinium</i> accounted for &gt; 60% of the species throughout the exposure period. However, the phytoplankton community structure was the least diverse among the DIC + IBU-exposed groups throughout the study. Peroxidase and glutathione-S-transferase activities were higher for Ibuprofen + Paracetamol, Diclofenac + Paracetamol, and Diclofenac + Ibuprofen + Paracetamol than for other treatments. Canonical correspondence analysis showed that nitrate and pH influenced phytoplankton population dynamics. The findings of this study highlight the risks posed by the presence of multiple drugs in aquatic environments. as their combined effects can significantly alter the structure and function of phytoplankton.</p>