Serum proteins are essential for maintaining osmotic pressure, regulating pH, transporting metabolites, and supporting immune responses. Studying the effects of plant-based diets on these proteins is crucial to understanding their impact on fish health and immune function. Methods: This study was conducted in a recirculation system, with rainbow trout distributed across nine tanks and fed three diets: fishmeal (control), medium plant meal (MPM; 40% of fishmeal replacement), and high plant meal (HPM; 80% of fishmeal replacement). Plasma protein and plasma glucose levels were measured at the initial and final stages, under both fasting (24 h after fast) and postprandial (6 h after fed) conditions, to assess dietary impacts. Additionally, the hepatosomatic index (HSI) was calculated at the end of the experiment to evaluate potential liver adaptations to the diets. Results: The initial protein and glucose levels were similar across all groups. However, by the end of the treatment, the fishmeal-fed group showed significantly higher total protein and globulin levels, while the albumin levels remained consistent across diet types. A significant interaction between sampling time and dietary treatment in fish reduced the clarity of dietary effects on postprandial plasma glucose levels. Furthermore, the HSI was significantly lower in fish fed the high plant meal (HPM) diet compared to the fishmeal and medium plant meal (MPM) groups, suggesting potential metabolic adaptation in response to plant-based diets. Conclusions: Replacing fishmeal with plant-based proteins in rainbow trout diets reduces total globulin and protein concentrations but leaves albumin unaffected, alongside reductions in fasting and postprandial glucose levels. The low growth and different HSI in fish fed plant-based diets highlights potential liver stress, emphasizing the need for further research to optimize sustainable aquaculture feeds while maintaining fish health and performance.