As a member state of the International Health Regulations 2005, Cambodia is continuously strengthening its capacity to respond to health emergencies and prevent the international spread of diseases. Despite this, Cambodia’s capacity to prevent, detect and rapidly respond to public health threats remained limited at the onset of the pandemic, as was the case in most countries. This paper describes epidemiological phases, response phases, strategy and lessons learnt in Cambodia between 27 January 2020 and 30 June 2022. We classified epidemiological phases in Cambodia into three phases, in which Cambodia responded using eight measures: (1) detect, isolate/quarantine; (2) face coverings, hand hygiene and physical distancing measures; (3) risk communication and community engagement; (4) school closures; (5) border closures; (6) public event and gathering cancellation; (7) vaccination; and (8) lockdown. The measures corresponded to six strategies: (1) setting up and managing a new response system, (2) containing the spread with early response, (3) strengthening the identification of cases and contacts, (4) strengthening care for patients with COVID-19, (5) boosting vaccination coverage and (6) supporting disadvantaged groups. Thirteen lessons were learnt for future health emergency responses. Findings suggest that 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 level of cooperation from the public. However, Cambodia needs to further improve its infrastructure for quarantining and isolating cases and close contacts and laboratory capacity for future health emergencies.