BACKGROUND: As the global burden of disease evolves, lower-resource countries like Nepal face a double burden of non-communicable and infectious disease. Rapid adaptation is required for Nepal's health system to provide life-long, person-centred care while simultaneously improving quality of infectious disease services. Social determinants of health be key in addressing health disparities and could direct policy decisions to promote health and manage the disease burden. Thus, we explore the association of social determinants with the double burden of disease in Nepal. METHODS: This is a retrospective, ecological, cross-sectional analysis of infectious and non-communicable disease outcome data (2017 to 2019) and data on social determinants of health (2011 to 2013) for 753 municipalities in Nepal. Multinomial logistic regression was conducted to evaluate the associations between social determinants and disease burden. RESULTS: The 'high-burden' combined double burden (non-communicable and infectious disease) outcome was associated with more accessible municipalities, (adjOR3.94[95%CI2.94-5.28]), municipalities with higher proportions of vaccine coverage (adjOR12.49[95%CI3.05-51.09]) and malnutrition (adjOR9.19E103[95%CI19.68E42-8.72E164]), lower average number of people per household (adjOR0.32[95%CI0.22-0.47]) and lower indigenous population (adjOR0.20[95%CI0.06-0.65]) compared to the 'low-burden' category on multivariable analysis. 'High-burden' of non-communicable disease was associated with more accessible municipalities (adjOR1.93[95%CI1.45-2.57]), higher female proportion within the municipality (adjOR1.69E8[95%CI3227.74-8.82E12]), nutritional deficiency (adjOR1.39E17[95%CI11799.83-1.64E30]) and malnutrition (adjOR2.17E131[95%CI4.41E79-1.07E183]) and lower proportions of population under five years (adjOR1.05E-10[95%CI9.95E-18-0.001]), indigenous population (adjOR0.32[95%CI0.11-0.91]), average people per household (adjOR0.44[95%CI0.26-0.73]) and households with no piped water (adjOR0.21[95%CI0.09-0.49]), compared to the 'low-burden' category on adjusted analysis. 'High burden' of infectious disease was also associated with more accessible municipalities (adjOR4.29[95%CI3.05-6.05]), higher proportions of population under five years (adjOR3.78E9[95%CI9418.25-1.51E15]), vaccine coverage (adjOR25.42[95%CI7.85-82.29]) and malnutrition (adjOR4.29E41[95%CI12408.29-1.48E79]) and lower proportions of households using firewood as fuel (adjOR0.39[95%CI0.20-0.79]) ('moderate-burden' category only) compared to 'low-burden'. CONCLUSIONS: While this study produced imprecise estimates and cannot be interpreted for individual risk, more accessible municipalities were consistently associated with higher disease burden than remote areas. Female sex, lower average number per household, non-indigenous population and poor nutrition were also associated with higher burden of disease and offer targets to direct interventions to reduce the burden of infectious and non-communicable disease and manage the double burden of disease in Nepal.