BACKGROUND: Diarrhea and typhoid, ancient water-borne diseases which are highly connected to rainfall are serious public health challenges in the blocks of Kalahandi district of Odisha, India. OBJECTIVES: Corroboration of rainfall and waterborne diseases are available in abundance; therefore, the objective of this article is to calculate the climate and disease vulnerability index (CDVI) value for each block of Kalahandi. METHODS: We have applied the livelihood vulnerability index with some modifications and classify the three major categories, i.e., exposure, sensitivity, and adaptive capacity into six subcategories. These six subcategories are further divided into 26 vulnerability indicators based on a detailed literature review. RESULTS: The result indicated that the Thuamul Rampur block, the southernmost part of the district is highly exposed to the annual and seasonal mean rainfall, and the Madanpur Rampur block lies in the northernmost part of the district is highly exposed to diarrhea and typhoid. Based on the calculation of the final CDVI value, nearly 50% of blocks of the Kalahandi district fall in the category of very high to high vulnerable zones. Furthermore, it has been observed that factors such as rainfall and disease distribution, vulnerable population and infrastructure, and education and health-care capacities had a notable influence on vulnerability. CONCLUSION: It is rare to find a health vulnerability-related study in India at this microlevel based on the suitable indicators selected for a tribal and backward region.