Background and Aims Calotropis procera, a resilient shrub of arid ecosystems, holds considerable potential for domestication, yet its genomic adaptation and climate resilience remain underexplored. This study aims to uncover the genetic variation and environmental adaptability of C. procera across heterogeneous habitats in the Indian Thar Desert, particularly in the context of ongoing climate change.Methods To investigate local adaptation, 134 core genotypes from 570 accessions were integrated with environmental data for genotype-environment association analyses. The study employed habitat suitability modelling, genotype-environment association analyses and projected genomic vulnerability under two climate change scenarios (SSP126 and SSP585). Candidate loci from both models were used to compute the adaptive index, genomic offset and risk of non-adaptedness across the landscape.Key Results Three genetically distinct clusters were identified, shaped by geographical and climatic factors. A total of 478 significant single nucleotide polymorphism-environment associations, predominantly linked to temperature and precipitation, revealed that multiple genomic signatures contribute to environmental adaptation. Spatial patterns of adaptive potential and vulnerability were mapped. Species distribution modelling projected a decline in suitable habitats by 2081 under SSP585. A significant linear correlation between genomic offset and population suitability was observed under SSP126 (2021, 2081) and SSP585 (2021); however, this relationship was absent under SSP585 (2081), underscoring the potential genetic erosion under more severe climate scenarios.Conclusion This study demonstrates spatial variation in the adaptive capacity of C. procera populations, emphasizing the relevance of landscape genomics in assessing climate resilience. This approach is crucial for predicting genetic vulnerability, guiding conservation priorities and supporting domestication strategies in arid environments under future climate scenarios.