Abstract Background Non-alcoholic steatohepatitis (NASH) has been recognised as a significant form of chronic liver disease and a common cause of cirrhosis and hepatocellular carcinoma, resulting in a considerable financial burden on healthcare resources. Currently, there is no information regarding the economic burden of NASH in low- and middle-income countries (LMICs). The aim of this study was to estimate the economic burden of NASH in Thailand as a lesson learned for LMICs. Methods To estimate the healthcare costs and prevalence of NASH with significant fibrosis (fibrosis stage ≥ 2) in the general Thai population, an eleven-state lifetime horizon Markov model with 1-year cycle length was performed. The model comprised Thai population aged 18 years and older. The cohort size was based on Thailand Official Statistic Registration Systems. The incidence of NASH, transitional probabilities, and costs-of-illness were based on previously published literature, including systematic reviews and meta-analyses. The age-specific prevalence of NASH was based on Thai NASH registry data. Costs were expressed in 2019 US Dollars ($). As we undertook analysis from the payer perspective, only direct medical costs were included. All future costs were discounted at an annual rate of 3%. A series of sensitivity analyses were performed. Results The estimated total number of patients with significant NASH was 2.9 million cases in 2019, based on a NASH prevalence of 5.74%. The total lifetime cost of significant NASH was $15.2 billion ($5,147 per case), representing approximately 3% of the 2019 GDP of Thailand. The probabilistic sensitivity analysis showed that the lifetime costs of significant NASH varied from $11.4 billion to $18.2 billion. Conclusions The economic burden associated with NASH is substantial in Thailand. This prompts clinicians and policy makers to consider strategies for NASH prevention and management.