Muscle fatigue and cognitive disturbances persist in patients after recovery from acute COVID-19 disease. However, there are no specific treatments for post-COVID fatigue. Objective: To evaluate the efficacy and safety of the health supplements ImmunoSEB (systemic enzyme complex)and ProbioSEB CSC3 (probiotic complex) in patients suffering from COVID-19 induced fatigue. A randomized, multicentric, double-blind, placebo-controlled trial was conducted in 200 patients with a complaint of post-COVID fatigue. The test arm (n= 100) received the oral supplements for14 days and the control arm (n= 100) received a placebo. Treatment efficacy was compared using the Chalder Fatigue scale (CFQ-11), at various time points from days 1 to 14. The supplemental treatment resulted in the resolution of fatigue in a greater percentage of subjects in the test vs. the control arm (91% vs. 15%) on day 14. Subjects in the test arm showed a significantly greater reduction in total as well as physical and mental fatigue scores at all time points vs. the control arm. The supplements were well tolerated with no adverse events reported. This study demonstrates that a14 days supplementation of ImmunoSEB + ProbioSEB CSC3 resolves post-COVID-19 fatigue and can improve patients’ functional status and quality of life.