Background: Studies have reported healthcare costs before and after mCRPC diagnosis in commercially insured populations, but no information is available about costs with progression through lines of therapy after mCRPC diagnosis. This study describes healthcare costs among men with mCRPC in the US Medicare population before mCRPC diagnosis, after diagnosis, and with progression through lines of therapy. Methods: Men newly diagnosed with mCRPC were identified in Medicare fee-for-service claims during 1/1/2014–6/30/2019. Adult men were required to have a diagnosis of prostate cancer, metastasis diagnosis, castration-resistance using a published claims-based algorithm, and continuous insurance coverage for ≥1 year before and ≥6 months after index mCRPC diagnosis unless patients died. Unadjusted all-cause healthcare costs (medical and pharmacy) per patient per year (PPPY) to Medicare inflated to 2019 dollars were described for the periods before mCRPC diagnosis, after diagnosis, and from the start of first-line (1L), second-line (2L), and third-line (3L) therapy with mCRPC life-prolonging treatments to the start of subsequent therapy or end of follow up. Results: Among 14,780 men with mCRPC, median age was 75 years, and the mean Quan-Charlson Comorbidity Index was 2.1. Median follow-up after mCRPC diagnosis was 17 months. During the follow up, 3,252 men had no life-prolonging treatment, 11,528 men initiated 1L mCRPC therapy, 6,275 initiated 2L, and 2,945 initiated 3L. Mean all-cause healthcare costs PPPY were $27,468 in the year before mCRPC diagnosis, $124,379 after mCRPC diagnosis, $102,380 among men without life-prolonging treatment after mCRPC diagnosis, $148,325 from the start of 1L to subsequent therapy or end of follow up, $160,118 from the start of 2L therapy, and $165,186 from the start of 3L therapy. Conclusions: Mean healthcare costs increased over 4-fold from before to after mCRPC diagnosis and increased steadily as patients progressed from first through third lines of mCRPC therapy. These findings help quantify the economic burden of mCRPC and contextualize the economic value of treatments that delay disease progression.