Background Severe acute respiratory syndrome corona virus (SARS‐CoV‐2) infection frequently causes severe and prolonged disease but only few specific treatments are available. We aimed to investigate safety and efficacy of a SARS‐CoV‐2‐specific siRNA‐peptide dendrimer formulation MIR 19® (siR‐7‐EM/KK‐46) targeting a conserved sequence in known SARS‐CoV‐2 variants for treatment of COVID‐19. Methods We conducted an open‐label, randomized, controlled multicenter phase II trial (NCT05184127) evaluating safety and efficacy of inhaled siR‐7‐EM/KK‐46 (3.7 mg and 11.1 mg/day: low and high dose, respectively) in comparison with standard etiotropic drug treatment (control group) in patients hospitalized with moderate COVID‐19 (N = 52 for each group). The primary endpoint was the time to clinical improvement according to predefined criteria within 14 days of randomization. Results Patients from the low‐dose group achieved the primary endpoint defined by simultaneous achievement of relief of fever, normalization of respiratory rate, reduction of coughing, and oxygen saturation of >95% for 48 h significantly earlier (median 6 days; 95% confidence interval CI: 5–7, HR 1.75, p = .0005) than patients from the control group (8 days; 95% CI: 7–10). No significant clinical efficacy was observed for the high‐dose group. Adverse events were reported in 26 (50.00%), 25 (48.08%), and 28 (53.85%) patients from the low‐, high‐dose and control group, respectively. None of them were associated with siR‐7‐EM/KK‐46. Conclusions siR‐7‐EM/KK‐46, a SARS‐CoV‐2‐specific siRNA‐peptide dendrimer formulation is safe, well tolerated and significantly reduces time to clinical improvement in patients hospitalized with moderate COVID‐19 compared to standard therapy in a randomized controlled trial. MIR 19® (siR‐7‐EM/KK‐46) is a siRNA‐peptide dendrimer formulation targeting a conserved sequence in known SARS‐CoV‐2 variants. Patients with moderate COVID‐19 inhaled 3.7 mg/day of siR‐7‐EM/KK‐46 achieved the primary composite endpoint significantly earlier. Significant clinical effect associated with siR‐7‐EM/KK‐46 at dose 3.7 mg/day was also accompanied by a significant reduction in viral load.Abbreviations: CI, confidence interval; COVID‐19, coronavirus disease 2019; Ct, cycle threshold; mg, milligram; MIR 19®, SARS‐CoV‐2‐specific siRNA‐peptide dendrimer formulation; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2; siRNA, small interfering RNA; RdRp, RNA‐dependent RNA polymerase