Background Some patients with prostate cancer regret their treatment choice. Treatment regret is associated with lower physical and mental quality of life. We investigated whether, in men with prostate cancer, spirituality is associated with lower decisional regret 6 months after treatment and whether this is, in part, because men with stronger spiritual beliefs experience lower decisional conflict when they are deciding how to treat their cancer. Methods One thousand ninety three patients with prostate cancer (84% white, 10% black, and 6% Hispanic; mean age = 63.18; SD = 7.75) completed measures of spiritual beliefs and decisional conflict after diagnosis and decisional regret 6 months after treatment. We used multivariable linear regression to test whether there is an association between spirituality and decisional regret and structural equation modeling to test whether decisional conflict mediated this relationship. Results Stronger spiritual beliefs were associated with less decisional regret (b = −0.39, 95% CI = −0.53, −0.26, P < .001, partial η2 = 0.024, confidence interval = −0.55, 39%, P < .001, partial η2 = 0.03), after controlling for covariates. Decisional conflict partially (38%) mediated the effect of spirituality on regret (indirect effect: b = −0.16, 95% CI = −0.21, −0.12, P < .001). Conclusions Spirituality may help men feel less conflicted about their cancer treatment decisions and ultimately experience less decisional regret. Psychosocial support post‐diagnosis could include clarification of spiritual values and opportunities to reappraise the treatment decision‐making challenge in light of these beliefs.