To evaluate the effect of Health Poverty Alleviation Project on the economic burden of disease among poor families and to provide references for further improvement of the Health Poverty Alleviation Project. The difference-in-differences with propensity score matching method was used to analyze 48 counties in Sichuan Province. Propensity score matching was first carried out with data from the Sichuan Provincial Information System for Medical Care for Low-Income Population and the New Rural Cooperative Medical Insurance data to identify the non-poor population closest to the poor population. Then, difference-in-difference method was used to determine the effect of the Health Poverty Alleviation Project. Health Poverty Alleviation Project reduced the total annual out-of-pocket (OOP) payments by 13.1% on average, the outpatient OOP payments by an average 2.4%, inpatient OOP payments by an average 19.5%, and the probability of incurring catastrophic health care expenditures by an average of 3.9% for low-income households. In addition, the program had a more significant effect in poverty-stricken counties than it did in non-poverty-stricken counties. Despite the significant effectiveness of the project, 12.1% of the low-income families still incurred catastrophic health expenditures after the program was implemented. Health Poverty Alleviation Project reduces the economic burden of disease for poor households, and it has a better effect on reducing the economic burden of poor households in poverty-stricken counties. However, a certain number of households still incurred catastrophic health expenditures. When consolidating and expanding the effects of Health Poverty Alleviation Project and monitoring medical expenses for poverty prevention, policymakers should focus on the households with catastrophic medical expenditures to prevent them from sinking back into poverty.