Objective During the early part of the COVID-19 pandemic, non-pharmacologic interventions were the strategies for the prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The Ministry of Ayush, Govt. of India, had advised Arsenicum album 30C, as a prophylactic to prevent COVID-19. This study was undertaken to evaluate the protective efficacy and safety of the Arsenicum album 30C. Methods We conducted a prospective, multicentre, cluster-randomized, parallel arm, community-based, open-label study involving apparently healthy individuals residing in containment areas of 7 cities of India. Clusters are defined as the population residing in the containment areas, who are under restriction for movement. 42 clusters were randomly assigned at 2:1 to the Arsenicum album 30C group (30 clusters) or to the control group (12 clusters, which received no specific therapy). The medicine was given twice daily for 7 days. The primary outcome was the incidence of COVID-19, as per the case definition notified by the National Centre for Disease Control, Government of India, during three weeks follow-up period. Results The analysis included 32186 individuals residing in 42 clusters (containment areas). A total of 22693 individuals of 30 clusters received Arsenicum album 30C and 9493 individuals of 12 clusters were observed in the control group. Results were similar in the medicine and control groups for age, gender, and comorbidity. The overall protective effect of the Arsenicum album 30C was 80.22% (95% confidence interval [CI], 71.16 to 86.44; 40 cases per 22693 [6.04 per 10000 person-weeks] in the Arsenicum album 30C group vs. 84 cases per 9493 [29.78 per 10000 person-weeks] in the control group). The protective effect of the Arsenicum album 30C against laboratory-confirmed COVID-19 was 68.22% (95% [CI], 49.64 to 80; 32 cases per 22693 [4.83 per 10000 person-weeks] in the Arsenicum album 30C group vs. 42 cases per 9493 [14.93 per 10000 person-weeks] in the control group). Adverse effects observed in both groups were mild and resolved without medication and sequelae. Conclusion Homeopathic medicine Arsenicum album 30C was associated with a decrease in the incidence and provided some protection against COVID-19 as compared to non-treatment. Further, randomized, double-blind, placebo-controlled trials may be conducted to validate the results of this study.