Objective: This review describes the COVID-19 epidemiology and response between 27 January 2020 and 30 June 2022, and analyses the lessons learned for future public health responses in Cambodia. Methods: We analysed the national COVID-19 database and reviewed literature. Results: We classified Cambodia's COVID-19 epidemiology into three phases. Phase 1 (27 January 2020 to 19 February 2021) was when COVID-19 was well contained, with only 578 cases, mainly imported (n = 320, 55.4%), and no deaths. Phase 2 (20 February 2021 to 31 October 2021) was when a large community outbreak occurred, with 255,792 cases and 2,805 deaths recorded. Phase 3 (1 November 2021 to 30 June 2022) was after the country's full re-opening, with 47,314 cases and 251 deaths. In phase 1, Cambodia responded using six non-pharmaceutical measures using the 5Es principle: Early detection, Early isolation, Early tracing, Early treatment, and Early education. Boosting the vaccination awareness campaign and coverage, and imposing a lockdown were the essential measures added to the above in phase 2. In phase 3, all non-pharmaceutical measures were lifted after high vaccination coverage of 93.1% of the population. Conclusion: Cambodia successfully contained the spread of SARS-CoV-2 in the first year and quickly attained high vaccine coverage by the second year of the response. The core of this success was the strong political will and high cooperation from the public. However, Cambodia needs to improve its medical infrastructure, human resources, and laboratory capacity for future health emergencies.