Over the past decade, Cambodia has seen a significant decline in its malaria burden. The government has established the goal of eliminating malaria in the country by 2025. With PMI/USAID support, Cambodia is implementing a package of interventions as part of its efforts. This assessment aimed to describe the cost of malaria elimination activities in Sampov Loun Operational District (OD) between July 2015 and March 2018, to describe the cost per malaria case detected under PMI programming, and to estimate the incremental cost-effectiveness of the elimination programme per Plasmodium falciparum (Pf) or P. vivax (Pv)/Pf mixed case averted under the Cambodia Malaria Elimination Programme (CMEP) and the U.S. President’s Malaria Initiative. Opportunity costs of government workers were also assessed to understand the theoretical cost of sustaining this programme through government efforts alone. We conducted an empirical micro-costing analysis based on elimination activities alone using CMEP internal project implementation data and corresponding epidemiologic data from July 2015 to March 2018 and empirical findings from implementation to date. We then constructed a cost model in Microsoft Excel using empirical data and used a cost-effectiveness decision tree to describe programme effective-ness in the first three years of implementation and to estimate efficacy for the subsequent year. The total cost of malaria elimination activities in Sampov Loun OD from July 2015 to March 2018 was $883,096. The cost per case of malaria detected in 2017 was $1,304. Including opportunity costs for government staff from July 2015 to March 2018, the total cost was $926,000. Under continued CMEP implementation, the projected future total cost of the program would be about $110,000 per year, or $0.64 per Sampov Loun resident. The incremental cost-effectiveness of the elimination programme was $28 for every additional Pf or Pv/Pf mix malaria case averted, compared to the no-CMEP proxy. CMEP activities are cost effective compared to the no-CMEP proxy, as shown through an incremental cost-effectiveness of $28 for every additional Pf or Pv/Pf mix malaria case averted. The total cost of the project is 0.93% of the total per capita spending on health in Cambodia and about 5% of all government health expenditure. Continuing investments in malaria will be needed at national level for stewardship and governance and at local level for ensuring programme readiness in case of malaria outbreaks.