Exposure to microorganisms such as Yersinia ruckeri can significantly affect bacterial infections in fish. Microplastics (MPs) may predispose fish to infection and act as carriers in pathogen transmission. Therefore, this study is designed to evaluate MPs’ effect on damage caused by exposure to Y. ruckeri in rainbow trout. In this study, blood biochemical parameters and hepatic oxidative biomarkers as clinical signs were measured in the fish co-exposed to Y. ruckeri (5 and 10% the median lethal dose (LD50)) and MPs (500 and 1000 mg Kg−1) for 30 days. There were no significant changes in the creatinine, triglyceride, cholesterol levels, and glutamic-pyruvic transaminase activity in the blood of fish infected with Y. ruckeri. In contrast, exposure to MPs had a significant effect on most clinical parameters. The total protein, albumin, globulin, total immunoglobulins, high-density lipoprotein, low-density lipoprotein, cholesterol levels, and γ-glutamyltransferase activity decreased, whereas glucose, triglyceride, and creatinine levels, and glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, alkaline phosphatase, and lactate dehydrogenase activities increased in the plasma of fish after co-exposure to MPs and Y. ruckeri. Dietary MPs combined with a Y. ruckeri challenge decreased catalase and glutathione peroxidase activities, and total antioxidant levels. However, superoxide dismutase activity and malondialdehyde contents increased in the hepatocyte of fish co-exposed to MPs and Y. ruckeri. This study suggests that fish exposure to MPs and simultaneous challenge with Y. ruckeri could synergistically affect clinical parameters.