Neglected Tropical Diseases (NTDs) and malaria, as tropical diseases, have long been major global public health challenges, particularly in low-income countries. Although the burden of NTDs and malaria has declined in recent years, significant health inequalities persist across regions. In the future, climate change may further exacerbate the burden of NTDs and malaria, with these burdens likely to disproportionately concentrate in low-income countries. This study aims to describe the global trends in the burden of NTDs and malaria, reveal health inequalities, and forecast future disease burdens. This study utilizes the latest data from the Global Burden of Disease Study (GBD) 2021 to assess the global trends and spatial distribution of NTDs and malaria burden from 1990 to 2021. Inequality analyses and frontier analysis were employed to evaluate disparities in disease burden and governance potential across countries, and the interactive effects between environmental risks and socio-economic factors on the burden of NTDs and malaria were explored in depth. Furthermore, the Bayes Age-Prior-Cohort model was used to forecast changes in disease burden from 2022 to 2041. From 1990 to 2021, the age-standardized DALY rate for NTDs and malaria declined from 1506.54 to 1020.27 per 100,000. Western Sub-Saharan Africa remains the most affected, contributing 51.18% of the global burden. Males have lower incidence but higher mortality rates compared to females. Despite improvements in global inequality, regional disparities persist. Environmental and socio-economic factors interact significantly, exacerbating the burden in vulnerable regions. The NTDs and malaria burden is projected to increase over the next 20 years, particularly in Middle and Low-middle Socio-Demographic Index (SDI) regions. Despite a global decline in the burden of NTDs and malaria, low-income countries, particularly in Western Sub-Saharan Africa, continue to experience significant health inequalities. Global climate change may exacerbate this burden, and these burdens will be disproportionately concentrated in tropical, poverty-stricken countries.