A high circulating cholesterol concentration is considered an important risk factor for the development of cardiovascular disease. Since lean fish intake and fish protein supplementation have been associated with lower cholesterol concentration in some but not all clinical studies, the main aim of this study was to investigate the effect of diets containing proteins from fish muscles and fish byproducts on the serum/plasma TC concentration in rodents. A systematic literature search was performed using the databases PubMed, Web of Science and Embase, structured around the population (rodents), intervention (type of fish and fraction, protein dose, duration), comparator (casein as control protein) and the primary outcome (circulating total cholesterol). Articles were assessed for risk of bias using the SYRCLE’s tool. A meta-analysis was conducted in Review Manager v. 5.4.1 (the Cochrane Collaboration) to determine the effectiveness of proteins from fish on the circulating TC concentration. Thirty-nine articles were included in the systematic review and meta-analysis, with data from 935 rodents. The risk of bias is unclear since few of the entries in the SYRCLE’s tool were addressed. Consumption of proteins from fish resulted in a significantly lower circulating TC concentration when compared to control groups (mean difference -0.24 mmol/l, 95% confidence interval -0.34, -0.15, P < 0.00001), with high statistical heterogeneity (I2 = 71%). To conclude, proteins from fish muscles and byproducts show promise as a functional dietary ingredient or supplement by preventing high cholesterol concentration in rodents, thus reducing one of the most important risk factors for developing cardiovascular disease.