Background: Prostate specific membrane antigen (PSMA) is a membrane-bound protease largely overexpressed in all prostate cancers. Differential expression of PSMA in tumor and non-tumor tissue has led to evolution of several targeted therapeutic interventions in metastatic castration resistant prostate cancer (mCRPC). Case Report: Here we present the case of 66-year-old male of advanced carcinoma prostate with multiple skeletal metastasis. He underwent bilateral orchidectomy and started on abiraterone followed by enzalutamide. Being unresponsive to both these treatments, he received 6 cycles of chemotherapy with docetaxel but had continuously rising PSA. His genomic analysis did not reveal any DNA repair defects. After performing ⁶⁸Ga-PSMA-PETCT scan, he was started on 177-Lu-PSMA therapy. On receiving three cycles of Lu-177 DKFZ-PSMA-617, good clinical and biochemical response was obtained. However, on further PSA rise he was started on actinium 225-PSMA therapy. Till date three cycles of Actinium-225 PSMA therapy has been given and ⁶⁸Ga-PSMA-PETCT scan demonstrated good partial response at metastatic sites with corresponding decrease in sPSA levels. The patient is now on follow up and receiving zoledronic acid at 3 months interval and is presently asymptomatic at the time of last follow up. Conclusion: PSMA directed radionuclide therapy is a promising treatment option in patients of mCRPC refractory to docetaxel therapy yielding excellent and durable biochemical control.