Low-fat diets, lipid-modifying nutraceuticals and a higher level of physical activity are often recommended to reduce dyslipidemia. A double-blind, randomized, crossover, controlled trial was designed to evaluate the independent and synergistic effects of Arthrospira ( Spirulina) maxima supplementation (4.5 g·day −1) with or without performing a physical exercise program ( PEP: aerobic exercise (3 days·week −1) + high-intensity interval training (2 days·week −1)) on blood lipids and BMI of 52 sedentary men with excess body weight. During six weeks, all participants were assigned to four intervention treatments ( Spirulina maxima with PEP (SE), placebo with PEP (Ex), Spirulina maxima without PEP (Sm), placebo without PEP (C; control)) and plasma lipids were evaluated spectrophotometrically pre- vs. post intervention in stratified subgroups (overweight, obese and dyslipidemic subjects). Pre/post comparisons showed significant reductions in all plasma lipids in the SE group, particularly in those with dyslipidemia ( p ≤ 0.043). Comparing the final vs. the initial values, BMI, total cholesterol, triglycerides and low-density lipoprotein cholesterol were decreased. High-density lipoprotein cholesterol increased in all treatment groups compared to C. Changes were observed mostly in SE interventions, particularly in dyslipidemic subjects ( p < 0.05). Spirulina maxima supplementation enhances the hypolipidemic effect of a systematic PEP in men with excess body weight and dyslipidemia.