• Multiple environmental stressors can affect fish health at different biological levels. • Parasitism and water temperature had limited effects on gudgeon health. • Trace metal contamination indirectly increased liver lesions through over-inflammation. • Combined contamination and temperature decreased fish growth. • Multiple stressors have complex interactive effects on fish health in human-altered rivers. Freshwater fish face multiple challenges in human-altered rivers such as trace metal contamination, temperature increase and parasitism. These multiple stressors could have unexpected interactive effects on fish health due to shared physiological pathways, but few studies investigated this question in wild fish populations. In this study, we compared 16 populations of gudgeon (Gobio occitaniae) distributed along perturbation gradients in human-altered rivers in the South of France. We tested the effects of single and combined stressors (i.e., metal contamination , temperature, parasitism) on key traits linked to fish health across different biological levels using a Structural Equation Modelling approach. Parasitism and temperature alone had limited deleterious effects on fish health. In contrast, fish living in metal-contaminated sites had higher metal bioaccumulation and higher levels of cellular damage in the liver through the induction of an inflammatory response. In addition, temperature and contamination had interactive negative effects on growth. These results suggest that trace metal contamination has deleterious effects on fish health at environmentally realistic concentrations and that temperature can modulate the effects of trace metals on fish growth. With this study, we hope to encourage integrative approaches in realistic field conditions to better predict the effects of natural and anthropogenic stressors on aquatic organisms.