Introduction: The incidence of diarrhea, a leading cause of morbidity and mortality in low-income countries such as Nepal, is temperature-sensitive, suggesting it could be associated with climate change. With climate change fueled increases in the mean and variability of temperature and precipitation, the incidence of water and food-borne diseases are increasing, particularly in sub-Saharan Africa and South Asia. This national-level ecological study was undertaken to provide evidence linking weather and climate with diarrhea incidence in Nepal. Method: We analyzed monthly diarrheal disease count and meteorological data from all districts, spanning 15 eco-development regions of Nepal. Meteorological data and monthly data on diarrheal disease were sourced, respectively, from the Department of Hydrology and Meteorology and Health Management Information System (HMIS) of the Government of Nepal for the period from 2002 to 2014. Time-series log-linear regression models assessed the relationship between maximum temperature, minimum temperature, rainfall, relative humidity, and diarrhea burden. Predictors with p-values < 0.25 were retained in the fitted models. Results: Overall, diarrheal disease incidence in Nepal significantly increased with 1 °C increase in mean temperature (4.4%; 95% CI: 3.95, 4.85) and 1 cm increase in rainfall (0.28%; 95% CI: 0.15, 0.41). Seasonal variation of diarrheal incidence was prominent at the national level (11.63% rise in diarrheal cases in summer (95% CI: 4.17, 19.61) and 14.5% decrease in spring (95% CI: −18.81, −10.02) compared to winter season). Moreover, the effects of temperature and rainfall were highest in the mountain region compared to other ecological regions of Nepal. Conclusion: Our study provides empirical evidence linking weather factors and diarrheal disease burden in Nepal. This evidence suggests that additional climate change could increase diarrheal disease incidence across the nation. Mountainous regions are more sensitive to climate variability and consequently the burden of diarrheal diseases. These findings can be utilized to allocate necessary resources and envision a weather-based early warning system for the prevention and control of diarrheal diseases in Nepal.