ObjectiveThe study contextualises the spatial heterogeneity and associated drivers of open defecation (OD) in India.DesignThe present study involved a secondary cross-sectional survey data from the fifth round of the National Family Health Survey conducted during 2019–2021 in India. We mapped the spatial heterogeneity of OD practices using LISA clustering techniques and assessed the critical drivers of OD using multivariate regression models. Fairlie decomposition model was used to identify the factors responsible for developing OD hot spots and cold spots.Setting and participantsThe study was conducted in India and included 636 699 sampled households within 36 states and union territories covering 707 districts of India.Primary and secondary outcome measuresThe outcome measure was the prevalence of OD.ResultsThe prevalence of OD was almost 20%, with hot spots primarily located in the north-central belts of the country. The rural–urban (26% vs 6%), illiterate-higher educated (32% vs 4%) and poor-rich (52% vs 2%) gaps in OD were very high. The odds of OD were 2.7 and 1.9 times higher in rural areas and households without water supply service on premises compared with their counterparts. The spatial error model identified households with an illiterate head (coefficient=0.50, p=0.001) as the leading spatially linked predictor of OD, followed by the poorest (coefficient=0.31, p=0.001) and the Hindu (coefficient=0.10, p=0.001). The high-high and low-low cluster inequality in OD was 38%, with household wealth quintile (67%) found to be the most significant contributing factor, followed by religion (22.8%) and level of education (6%).ConclusionThe practice of OD is concentrated in the north-central belt of India and is particularly among the poor, illiterate and socially backward groups. Policy measures should be taken to improve sanitation practices, particularly in high-focus districts and among vulnerable groups, by adopting multispectral and multisectoral approaches.