Background: Hypertension is a major risk factor for chronic kidney disease (CKD) and disproportionately affects African American women, contributing to disparities in kidney health outcomes. The biological mechanisms connecting hypertension to reduced kidney function, particularly in understudied populations, remain poorly understood. This study leverages transcriptomic analyses to uncover shared molecular signatures associated with hypertension and kidney function, focusing on female-specific profiles. Methods: The study analyzed whole-blood mRNA sequencing data from a cohort of 344 African American women, divided equally into discovery (n = 172) and validation (n = 172) datasets, along with 147 African American men. Differential expression (DE) analyses were performed to identify mRNAs associated with hypertension and kidney function (measured as eGFR). Female-specific findings were determined by comparing results between females and males. Pathway enrichment analyses were subsequently conducted to link the identified mRNAs to key biological mechanisms. Results: Comparative analyses revealed unique transcriptomic profiles in females, underscoring the role of sex-specific factors in disease progression. DE analyses identified 95 female-specific genes associated with both hypertension and eGFR. Subsequent pathway enrichment analysis with the 95 genes revealed key pathways related to fibrosis, inflammation, lipid metabolism, and endothelial dysfunction. The list of 95 includes TGF-{beta}1 and PNPLA2 implicated in fibrotic and metabolic dysregulation, and immune system players such as IL32 and TNFSF12 that amplify inflammation and kidney injury. Conclusions: This study provides novel insights into the transcriptomic mechanisms underlying hypertension and kidney function in African American women. The findings emphasize the importance of addressing sex-specific and population-specific molecular mechanisms to inform precision medicine approaches and reduce health disparities hypertension-related impaired kidney function. Future research should prioritize experimental validation and longitudinal studies to further elucidate these pathways.