In 2017, the National Patient Safety Implementation Framework (NPSIF) was introduced in India to ensure patient safety at different levels of the health care delivery system by 2025. Evaluating the implementation status, feasibility, and challenges and obtaining suggestions for improvement are key to the successful and sustainable implementation of any national health framework. Hence, we explored the facilitators and challenges in implementing the NPSIF and sought suggestions to address the challenges. We adopted a descriptive qualitative approach to inquire about NPSIF implementation. Health care workers were selected using maximum variability sampling from 18 secondary- and tertiary-level public health care facilities in Tamil Nadu, India. From August to October 2021, we conducted a total of 80 key informant interviews and in-depth interviews with the relevant officers in-charge and HCWs of varied cadres. Facilitating factors reported were facilities obtaining/working toward quality certification; availability of standard protocols and checklists; and government rewards for the best-performing hospitals, doctors, and staff. Major implementation challenges reported were staff shortages; lack of infrastructure, facilities, and equipment; lack of awareness about patient safety, noncompliance to standard guidelines, and lack of patient cooperation. Recommendations suggested to overcome these challenges included providing educational materials to patients, offering regular continuing medical education and training, improving record maintenance, having a dedicated staff/team and surveillance system setup for patient safety and dedicated staff for data entry, filling existing staff vacancies, and using a carryover option for funding. Based on the current situation of patient safety practices in public health facilities in Tamil Nadu, it will be difficult to achieve full-scale implementation of the NPSIF by 2025. However, as a first step, a core patient safety committee can be formed at the state level to develop a Gantt chart for implementation based on the priorities over the next 2 years.