Background Inactivating alterations in SPOP frequently occur in prostate cancer and promote increased dependency on androgen receptor (AR)‐mediated oncogenic signaling. The presence of SPOP mutation (SPOP‐mutant SPOP‐mut) may therefore impact therapeutic outcomes with AR‐directed therapies and docetaxel in metastatic castration‐resistant (mCRPC). Methods This was a retrospective study of mCRPC patients treated at an urban academic hospital (n = 103). Patients underwent tumor DNA sequencing to determine SPOP mutational status (SPOP‐mut). Outcomes measured were overall survival (OS) from diagnosis and treatment with second‐generation AR signaling inhibitor (ARSI) or docetaxel and time to PSA progression (prostate‐specific antigen‐progression‐free survival PSA‐PFS) compared by SPOP status using Kaplan–Meier curves and log‐rank test. The univariable and multivariable Cox proportional hazard model evaluated the association of SPOP mutation and outcomes adjusted for clinicopathologic features. Results SPOP‐mut was associated with longer PSA‐PFS in mCRPC (median 1.79 vs. 0.84 years; p = 0.06) and multivariate analysis (hazard ratio HR = 0.37; 95% confidence interval CI: 0.17–0.84; p = 0.02). SPOP‐mut demonstrated a higher median PSA decline compared to SPOP wild‐type (median decline 100% vs. 92%, p = 0.02). SPOP‐mut was not associated with OS from the start of ARSI or docetaxel (median OS not reached vs. 2.0 years) or PSA‐PFS on docetaxel (median PSA‐PFS 0.4 vs. 0.5 years) in mCRPC. The majority of SPOP mutations were identified in African American (AA) patients (69.2%) compared to Caucasian patients (30.8%). Race‐associated multivariate analysis revealed no significant differences in OS from the start of ARSI or the start of docetaxel and no differences in ARSI or docetaxel PSA‐PFS between AA and Caucasian patients. Molecular profiling demonstrated that AA patients had a higher frequency of SPOP mutations and greater heterogeneity of SPOP variants within the coding sequence. Analysis of concurrent genomic alterations revealed that SPOP mutations co‐occur with APC mutations (p = 0.001) and alterations in the Wnt pathway (p = 0.017). Conclusions Inactivating mutations in SPOP are associated with better response to ARSI treatment in mCRPC overall. Additional analysis with a larger cohort is needed to evaluate the association of SPOP status and outcomes with docetaxel. Race‐associated clinical outcomes and molecular features were observed, suggesting the benefit of biomarker‐directed therapy selection for individualized patient subsets in guiding treatment decisions for mCRPC patients.