Background: Outbreak of SARS-CoV-2 is Janapadoddhwamsa Vikara (epidemic disease) in Ayurveda, where Rasayana drugs (immunomodulators or rejuvenating therapy) have been advocated for controlling the diseases. Therefore, Guduchi Ghan Vati, containing a drug Guduchi (Tinospora cordifolia), a plant is selected for prevention of COVID-19. Objectives: To know the efficacy and safety of Ayurvedic intervention i.e. Guduchi Ghan Vati in prevention of COVID-19 infection among the community of containment areas. Methods: It is an open label, prospective, non-randomized, community based interventional study, carried out from 06 May to 23 June, 2020, in a containment zone Bijhari area of District Hamirpur of Himachal Pradesh, India. Guduchi Ghan Vati was provided to the community in dose of 500 mg twice a day with luke warm water on empty stomach for 30 days. Their demographic and health related data and Follow up of the same subjects was done on the 30th day through telephonic interviews using the E-format (google forms). Results: Total 1165 participants’ data were analysed to assess the efficacy and safety of Guduchi Ghan Vati. In the sample 85.2 % participants had no systemic disorders whereas 13.8 % participants were taking concomitant medicines for other morbidities. Incidence of COVID-19 positive cases was only 0.1% (n=01). Conclusion: Ayurvedic intervention (Guduchi Ghan Vati) was found to be safe and effective as a prophylactic measure for COVID-19 infection. This intervention was helpful in improving physical and psychological well-being with minimal adverse drug Reaction/Adverse Effect.