Abstract Objective: This study aimed to asses the impact of a physical barrier-based infection prevention and control (IPC) intervention in patient wards at a tertiary care center on patient-to-patient coronavirus disease-2019 (COVID-19) transmission and cluster formation. Materials and Methods: A quasi-experimental study was conducted at a 1300-bedded South Indian tertiary care center. Barrier curtains were deployed between ward beds, accompanied by a social interaction protocol, at eight locations, each containing eleven 4-bedded cubicles accommodating 44 patient beds. A surveillance team daily audited adherence to mask usage, barrier curtains, and the social interaction protocol using a predefined checklist. An effective implementation hybrid design was employed to evaluate clinical impact (cluster formation) and implementation effectiveness (adherence to interventions) between the pre-implementation and post-implementation phases. Results: During the pre-implementation and post-implementation periods, 2398 and 1024 positive COVID-19 cases were recorded in the selected areas, respectively, with an average monthly positivity rate of 40%. The number of clusters decreased from three clusters with an average of 11.3 positive cases per cluster in the pre-implementation period to no clusters in the post-implementation period. Implementation effectiveness showed compliance rates of 90% for barrier curtain placement and 100% for the social interaction protocol. Conclusion: This study confirms that physical barriers, specifically curtains, are effective measures against nosocomial COVID-19 transmission. It underscores the importance of adopting context-specific, cost-effective strategies, especially in low-to-middle-income countries, and provides a strong rationale for further research and implementation of such interventions.