Natural environments are subject to a range of anthropogenic stressors, with pharmaceutical pollution being among the fastest-growing agents of global change. However, despite wild animals living in complex multi-stressor environments, interactions between pharmaceutical exposure and other stressors remain poorly understood. Accordingly, we investigated effects of long-term exposure to the pervasive pharmaceutical contaminant fluoxetine (Prozac) and acute temperature stress on reproductive behaviors and activity levels in the guppy (Poecilia reticulata). Fish were exposed to environmentally realistic fluoxetine concentrations (measured average: 38 or 312 ng/L) or a solvent control for 15 months using a mesocosm system. Additionally, fish were subjected to one of three acute (24 h) temperature treatments: cold stress (18 °C), heat stress (32 °C), or a control (24 °C). We found no evidence for interactive effects of fluoxetine exposure and temperature stress on guppy behavior. However, both stressors had independent impacts. Fluoxetine exposure resulted in increased male coercive copulatory behavior, while fish activity levels were unaffected. Under cold-temperature stress, both sexes were less active and males exhibited less frequent reproductive behaviors. Our results demonstrate that long-term exposure to a common pharmaceutical pollutant and acute temperature stress alter fundamental fitness-related behaviors in fish, potentially shifting population dynamics in contaminated ecosystems.