Androgen receptor (AR) inhibitors represent the mainstay of prostate cancer treatment. In a genome-wide CRISPR-Cas9 screen using LNCaP prostate cancer cells, loss of co-repressor conferred resistance to AR antagonists apalutamide and enzalutamide. Genes differentially expressed upon loss share AR as the top transcriptional regulator, and loss rescued the expression of a subset of androgen-responsive genes upon enzalutamide treatment. GR expression was strongly upregulated upon AR inhibition in a -negative background. This was consistent with binding of TLE3 and AR at the locus. Furthermore, GR binding was observed proximal to TLE3/AR-shared genes. GR inhibition resensitized cells to enzalutamide. Analyses of patient samples revealed an association between TLE3 and GR levels that reflected our findings in LNCaP cells, of which the clinical relevance is yet to be determined. Together, our findings reveal a mechanistic link between TLE3 and GR-mediated resistance to AR inhibitors in human prostate cancer.