Abstract Background The COVID-19 pandemic has prompted a re-evaluation of infection prevention and control (IPC) in general practices, highlighting the need for comprehensive IPC implementation. This study aimed to evaluate healthcare workers’ (HCWs) experiences and perspectives regarding IPC in general practices before and during the COVID-19 pandemic, and its implications for post-pandemic IPC implementation. Methods This qualitative study involved semi-structured, in-depth interviews during two time periods: (1) prior to the COVID-19 pandemic (July 2019-February 2020), involving 14 general practitioners (GPs) and medical assistants; and (2) during the COVID-19 pandemic (July 2022-February 2023), including 22 GPs and medical assistants. Data analysis included thematic analysis that addressed multiple system levels. Results Findings indicated a shift towards comprehensive IPC implementation and organisation during the pandemic compared to the pre-pandemic period. Since the Omicron variant, some general practices maintained a broad set of IPC measures, while others released most measures. HCWs’ future expectations on post-pandemic IPC implementation varied: some anticipated reduced implementation due to the desire to return to the pre-pandemic standard, while others expected IPC to be structurally scaled up during seasonal respiratory epidemics. Main contextual challenges included patient cooperation, staff shortages (due to infection), shortages of IPC materials/equipment, and frequently changing and ambiguous guidelines. Key lessons learned were enhanced preparedness (e.g., personal protective equipment supply), and a new perspective on care organisation (e.g., digital care). Main recommendations reported by HCWs were to strengthen regional collaboration within primary care, and between primary care, public health, and secondary care. Conclusion HCWs’ experiences, perspectives and recommendations provide insights to enhance preparedness for future epidemics and pandemics, and sustain IPC in general practices. ...