Contamination of aquatic environments by pharmaceuticals is increasingly being recognised as a global threat. The antidepressant fluoxetine is one such pharmaceutical that has not only been frequently detected in aquatic ecosystems globally, but has also been found to alter the behaviour of exposed wildlife. However, few studies to date have explored fluoxetine exposure beyond 35 days. This is surprising given that fluoxetine is highly resistant to degradation and, as a result, has the potential to persist in the environment and contaminate exposed wildlife for prolonged periods. Accordingly, we aimed to examine the impacts of multigenerational fluoxetine exposure on the behaviour, metabolic rate, and morphology of male guppies, Poecilia reticulata. Fish were exposed to one of three fluoxetine treatments—an unexposed freshwater control (0 ng/L), low fluoxetine (30 ng/L), or high fluoxetine (300 ng/L)—for 8 months (representing 2–3 overlapping generations) in a semi-natural mesocosm system. In the first assay, we examined predator inspection behaviour and activity in the presence or absence of a predatory spangled perch, Leiopotherapon unicolor. We then observed exploratory behaviour and activity in a novel environment (a maze arena). Metabolic rate and morphology (mass, standard length, and scaled mass index) were also measured following behavioural trials. Fluoxetine exposure did not significantly alter behaviour in either the predator assay or the maze assay. However, predator treatment (i.e., predator present versus absent) influenced behaviour, whereby fish entered a 5 cm zone surrounding a designated predator compartment faster—but spent less time in total in this area—when the predator was present. Finally, fluoxetine exposure did not significantly affect metabolic rate, mass, or standard length. However, we detected an effect of fluoxetine on scaled mass index. Overall, these findings underscore the importance of conducting longer-term exposure studies when considering the impacts of emerging environmental pollutants, such as pharmaceuticals.