Aim To assess viral clearance, pharmacokinetics, tolerability and symptom evolution following ensovibep administration in symptomatic COVID‐19 outpatients. Methods In this open‐label, first‐in‐patient study a single dose of either 225 mg (n = 6) or 600 mg (n = 6) of ensovibep was administered intravenously in outpatients with mild‐to‐moderate COVID‐19 symptoms. Pharmacokinetic profiles were determined (90‐day period). Pharmacodynamic assessments consisted of viral load (qPCR and cultures) and symptom questionnaires. Immunogenicity against ensovibep and SARS‐CoV‐2‐neutralizing activity were determined. Safety and tolerability were assessed throughout a 13‐week follow‐up. Results Both doses showed similar pharmacokinetics (first‐order) with mean half‐lives of 14 (SD 5.0) and 13 days (SD 5.7) for the 225‐ and 600‐mg groups, respectively. Pharmacologically relevant serum concentrations were maintained in all subjects for at least 2 weeks postdose, regardless of possible immunogenicity against ensovibep. Viral load changes from baseline at day 15 were 5.1 (SD 0.86) and 5.3 (SD 2.2) log10 copies/mL for the 225‐ and 600‐mg doses, respectively. COVID‐19 symptom scores decreased from 10.0 (SD 4.1) and 11.3 (SD 4.0) to 1.6 (SD 3.1) and 3.3 (SD 2.4) in the first week for the 225‐ and 600‐mg groups, respectively. No anti‐SARS‐CoV‐2 neutralizing activity was present predose and all patients had SARS‐CoV‐2 antibodies at day 91. Adverse events were of mild‐to‐moderate severity, transient and self‐limiting. Conclusion Single‐dose intravenous administration of 225 or 600 mg of ensovibep appeared safe and well tolerated in patients with mild‐to‐moderate COVID‐19. Ensovibep showed favourable pharmacokinetics in patients and the pharmacodynamic results warrant further research in a larger phase 2/3 randomized‐controlled trail.