Characterized by the accumulation of somatic mutations in blood cell lineages, clonal hematopoiesis (CH) of indeterminate potential (CHIP) is frequent in ageing, involves expansion of mutated hematopoietic stem and progenitor cells (HSC/Ps) that leads to an increased risk of hematologic malignancy. However, risk factors that contribute to CHIP-associated CH are poorly understood. Obesity induces a pro-inflammatory state and fatty bone marrow (FBM), which may influence CHIP-associated pathologies. We analyzed exome sequencing and clinical data from 47,466 individuals with validated CHIP in UK Biobank. CHIP was present in 5.8% of the study population and was associated with a significant increase in waist-to-hip ratio (WHR). Mouse models of obesity and CHIP driven by heterozygosity of Tet2, Dnmt3a, Asxl1 and Jak2 resulted in exacerbated expansion of mutant HSC/Ps due in part to excessive inflammation. Our results show that obesity is highly associated with CHIP and a pro-inflammatory state can potentiate progression of CHIP to more significant hematologic neoplasia. Calcium channel blocker, nifedipine or SKF-96365, either alone or in combination with metformin, MCC950 or anakinra (IL-1 receptor antagonist), suppressed the growth of mutant CHIP cells and partially restored normal hematopoiesis. Targeting CHIP mutant cells with these drugs could be a potential therapeutic approach to treat CH and its associated abnormalities in obese individuals.