APOL1 alleles G1 and G2 are associated with faster progression to lupus nephritis (LN)-associated end-stage renal disease (LN-ESRD) in African Americans. Increased levels of type I interferons (IFNs) and nucleosome-associated double-stranded DNA (dsDNA) fragments (nsDNA) are the hallmark of this disease. Here, we identify cyclic GMP-AMP synthase (cGAS) and interferon-inducible protein 16 (IFI16) as the major DNA sensors in human immortalized podocytes. We also show that nsDNA triggers the expression of APOL1 and IFNβ via IRF3 activation through the cGAS/IFI16-STING pathway. We demonstrate that maximal APOL1 expression also requires the activation of type I IFN receptor (IFNAR) and STAT1 signaling triggered by IFNβ produced in response to nsDNA, or by exogenous IFNβ. Finally, we show that STAT1 activation is sufficient to upregulate IFI16, subsequently boosting APOL1 expression through a positive feedback mechanism. Collectively, we find that nsDNA-induced APOL1 expression is mediated by both IFNβ-independent and dependent signaling pathways triggered by activation of the cGAS/IFI16-STING pathway. We propose that simultaneous inhibition of STING and the IFNAR-STAT1 pathway may attenuate IFI16 expression, reduce IFI16-cGAS cross-talk, and prevent excessive APOL1 expression in human podocytes in response to nsDNA.