BACKGROUND: With an increasing burden of non-communicable disease in Nepal and limited progress towards universal health coverage, country- and disease-specific estimates of financial hardship related to healthcare costs need to be evaluated to protect the population effectively from healthcare-related financial burden. OBJECTIVES: To estimate the cost and economic burden of illness and to assess the inequality in the financial burden due to catastrophic health expenditure from 1995 to 2010 in Nepal. METHODS: This study used nationally representative Nepal Living Standards Surveys conducted in 1995 and 2010. A Bayesian two-stage hurdle model was used to estimate average cost of illness and Bayesian logistic regression models were used to estimate the disease-specific incidence of catastrophic health payment and impoverishment. The concentration curve and index were estimated by disease category to examine inequality in healthcare-related financial hardship. FINDINGS: Inflation-adjusted mean out-of-pocket (OOP) payments for chronic illness and injury increased by 4.6% and 7.3%, respectively, while the cost of recent acute illness declined by 1.5% between 1995 and 2010. Injury showed the highest incidence of catastrophic expenditure (30.7% in 1995 and 22.4% in 2010) followed by chronic illness (12.0% in 1995 and 9.6% in 2010) and recent acute illness (21.1% in 1995 and 7.8% in 2010). Asthma, diabetes, heart conditions, malaria, jaundice and parasitic illnesses showed increased catastrophic health expenditure over time. Impoverishment due to injury declined most (by 12% change in average annual rate) followed by recent acute illness (9.7%) and chronic illness (9.6%) in 15 years. Inequality analysis indicated that poorer populations with recent acute illness suffered more catastrophic health expenditure in both sample years, while wealthier households with injury and chronic illnesses suffered more catastrophic health expenditure in 2010. CONCLUSION: To minimize the economic burden of illness, several approaches need to be adopted, including social health insurance complemented with an upgraded community-based health insurance system, subsidy program expansion for diseases with high economic burden and third party liability motor insurance to reduce the economic burden of injury.