The use of convalescent plasma (CP) has been considered for its immunological mechanisms that could benefit patients in moderate and severe stages of COVID-19. This study evaluated the safety and efficacy of the use of donor CP for COVID-19. A double-blind, randomized controlled clinical trial was conducted from May to October 2020. Thirty-nine participants with moderate (II) and severe (III) stages of COVID-19 confirmed by RT-PCR were included. The study randomization rate was set at 3:1. CPs were chosen for application with a neutralizing antibody titer of ≥1:32. We observed a significantly lower 21-day post-transfusion mortality HR: 0.17 (95.0% CI [0.07-0.45, p < 0.001]) in the group receiving CP compared with the control group; protective units (PU) in the group receiving convalescent plasma after seven days were significantly higher (512 (32-16,384) vs. 96 (32-256), p = 0.01); the PAO2/FIO2 index showed a significant improvement in the group receiving CP (251.01 (109.4) vs. 109.2 (62.4), p < 0.001, in the control group). CP is safe and effective, as it decreased mortality in the CP group compared with the control group.