The study analyzes the spatial clustering and risk factors of infant mortality across high-focus states of India, using the Annual Health Survey (2010–2011), Census of India (2011), and District Level Household and Facility Survey-3 (2007–2008). Research has found substantial spatial autocorrelation across the districts and identified the “hot spots” characterized by higher infant mortality rate (IMR) in the districts of the central region (Uttar Pradesh and Madhya Pradesh) of India. This study has considered several theoretical perspectives and implements a series of spatial regression models that allows accounting for household amenities and mother/child and health facility variables to determine the key risk factors of infant mortality. Our empirical analysis underscores the importance of the infrastructure of the health facility in improving the infant mortality scenario of the districts. The regression results show that the districts with a higher proportion of 24-h functioning primary healthcare centers have overall less infant mortality. In addition, the absence of drinking water from a treated source, unavailability of toilet facilities, and higher proportion of people in the bottom wealth quintile in the household were adversely associated with the IMR. In conclusion, reduction of infant mortality would be possible only if area-specific measures would be adopted on those clusters of districts where infant mortality is high irrespective of the state they belong to.