ObjectiveSystemic lupus erythematosus (SLE), an autoimmune disease with incompletely understood etiology, has a strong genetic component. Although genome‐wide association studies (GWASs) have revealed multiple SLE susceptibility loci and associated single‐nucleotide polymorphisms (SNPs), the precise causal variants, target genes, cell types, tissues, and mechanisms of action remain largely unknown.MethodsHere, we report a comprehensive post‐GWAS analysis using extensive bioinformatics, molecular modeling, and integrative functional genomic and epigenomic analyses to optimize fine‐mapping. We compile and cross‐reference immune cell–specific expression quantitative trait loci (cis– and trans–expression quantitative trait loci) with promoter capture high‐throughput capture chromatin conformation (PCHi‐C), allele‐specific chromatin accessibility, and massively parallel reporter assay data to define predisposing variants and target genes. We experimentally validate a predicted locus using CRISPR/Cas9 genome editing, quantitative polymerase chain reaction, and Western blot.ResultsAnchoring on 452 index SNPs, we selected 9,931 high linkage disequilibrium (r² > 0.8) SNPs and defined 182 independent non‐human leukocyte antigen (HLA) SLE loci. The 3,746 SNPs from 143 loci were identified as regulating 564 unique genes. Target genes are enriched in lupus‐related tissues and associated with other autoimmune diseases. Of these, 329 SNPs (106 loci) showed significant allele‐specific chromatin accessibility and/or enhancer activity, indicating regulatory potential. Using CRISPR/Cas9, we validated reference SNP identifier 57668933 (rs57668933) as a functional variant regulating multiple targets, including SLE‐risk gene ELF1 in B cells.ConclusionWe demonstrate and validate post‐GWAS strategies for using multidimensional data to prioritize likely causal variants with cognate gene targets underlying SLE pathogenesis. Our results provide a catalog of significantly SLE‐associated SNPs and loci, target genes, and likely biochemical mechanisms to guide experimental characterization.