American men of African genomic ancestry (AA) experience significantly more aggressive prostate cancer (PCa) than European American (EA) men. The basal and genomic 1,25-dihydroxyvitamin D₃ (1,25D₃) VDR cistromes are distinct between AA and EA PCa, potentially underpinning this disparity. Surveying ~1,500 coregulators across AA and EA PCa clinical cohorts identified ~20 uniquely altered in AA PCa, prominently including SMARCA5 and its partner BAZ1A. SMARCA5 is the ATPase subunit of ISWI complexes, including WICH and NoRC, which drive nucleosome phasing to control chromatin accessibility. To test how ancestry shapes SMARCA5 function, we performed CRISPR activation in AA (RC43T, RC77T) and EA (LNCaP) PCa models. RIME proteomics revealed selective assembly of SMARCA5 with WICH and NoRC complexes in AA cells only; NoRC being critical for heterochromatin boundary establishment. SMARCA5 CUT&RUN aligned to the human pangenome revealed ancestry-specific cistromes enriched for nuclear receptor motifs, including VDR, in AA but not EA cells. ATAC-Seq analyses demonstrated that 1,25D₃ exerts opposing effects on nucleosome-free regions (NFR) at promoters in LNCaP versus RC43T cells, and that SMARCA5 activation reduces NFR at active enhancers and promoters selectively in AA cells reflecting its role to ensure currect phasing. Critically, a significant SMARCA5 and 1,25D₃ interaction on NFR occupancy was detected exclusively in AA cells, suggesting that SMARCA5-mediated nucleosome phasing is permissive of 1,25D₃-driven activating complexes. RNA-Seq following combined SMARCA5 activation and 1,25D₃ treatment revealed a strong luminal differentiation program unique to AA PCa, with GSEA confirming enrichment of nuclear receptor signaling terms. SMARCA5-controlled VDR target genes included differentiation-associated miRNAs (e.g., miR-200c). Integrated ATAC- and RNA-Seq analyses showed luminal genes as dominant contributors to active enhancer–transcriptome correlations in AA PCa, validated by random forest modelling. Ancestry-stratified clinical cohorts spanning African, AA, and EA PCa demonstrated significant associations between vitamin D levels, SMARCA5-dependent gene signatures, and tumour grade. These findings establish that ancestry-selective SMARCA5 downregulation disrupts ISWI complex composition, impairs nucleosome phasing, and rewires transcriptional responses to 1,25D₃-VDR signaling, and represents an ancestry-stratified chromatin axis with biomarker and therapeutic relevance in AA PCa.