Background: The Indian Council of Medical Research (ICMR), under the Ministry of Health and Family Welfare, recommended chemoprophylaxis with Hydroxychloroquine (HCQ) for asymptomatic healthcare workers treating patients with suspected or confirmed COVID-19 disease during the initial period of the pandemic. Compliance remains a major determining factor behind the success of any Community prophylaxis program. Objective: The study aimed to assess the extent of compliance with the Hydroxychloroquine (HCQ) prophylaxis schedule as per ICMR guidelines among healthcare workers and to find out the factors associated with compliance. Methods: Informed consent was obtained from the study participants, and a questionnaire on parameters and associated factors affecting compliance were filled out by every study participant upon completion of their HCQ prophylaxis. Results: A total of 160 participants were enrolled in the study. The majority of the staff enrolled was the nursing staff (34%). 66% of the total participants were involved in the care of the suspected or confirmed case of COVID-19. The major source of information about HCQ prophylaxis for COVID- 19 infection among all the participants was from the Institutional circular (56%). 10% of healthcare workers believed that HCQ could give them 100% prevention against COVID-19 infection. 56% of the enrolled healthcare workers consumed the medicine on the same day of collection throughout the schedule. 24% of enrolled healthcare workers completed the full course as per ICMR guidelines. The most motivating factor for compliance was the presence of cases of COVID-19 in the hospital. The most common factor for lack of compliance among enrolled healthcare workers was cited to be no contact with COVID-19-positive patients. Conclusion: In our study, 24% of healthcare workers enrolled for HCQ prophylaxis completed the full course of the prescribed regimen as per ICMR guidelines. The main reason for the lack of compliance was the absence of direct contact with COVID-19-positive patients, followed by fear of ADRs.