The purpose of this study was to examine the effects of two arginine-based supplements on the fatigue level of patients following the COVID-19 infection. This is a prospective study of the SARS-CoV-2-infected patients divided into two groups (according to family physicians’ prescriptions, Group 1 of patients were treated with Astenor Energy®containing arginine aspartate, B6 vitamin, biotin and magnesium, and Group 2 of patients were treated with Astenor Forte®containing L-arginine and malic acid). The patients visited their family physicians from October 2021 to January 2022, complaining of physical and/or mental fatigue following the COVID-19 infection. We recorded 505 patients (146 patients in Group 1 and 359 patients in Group 2) and analyzed the fatigue level using the Fatigue Assessment Scale (FAS) through its total (FAS-T), mental (FAS-M) and physical (FAS-P) scores, at baseline and after three months of treatment. There was no difference between the two groups in terms of age (p= 0.265), but more men were included in Group 1 than in Group 2 (p= 0.001). The patients from Group 2 were significantly more likely to be treated at home than those included in Group 1 (89.7% vs. 65.1%,p< 0.0001) because of the lower severity of the COVID-19 infection (asymptomatic or mild: 82.5% vs. 48.7%,p< 0.0001). After 3 months of treatment, patients indicated no fatigue in the higher percentage compared to than at the baseline (68.7% vs. 27.7%), and the fatigue level significantly decreased both in Group 1 (median baseline 33.0 vs. follow-up 17.00,p< 0.0001) and Group 2 (median baseline 25.0 vs. follow-up 17.00,p< 0.0001). These findings suggest that supplements with L-arginine may be proposed as a remedy to restore physical and mental performance affected by the fatigue burden in people with COVID-19 or following the COVID-19 infection.