Objective Lutetium-177 (Lu-177) prostate-specific membrane antigen (Lu-177 PSMA) is a novel targeted treatment for patients with metastatic castration-resistant prostate cancer (CRPC). The purpose of the study was to determine the molecular volumetric Gallium-68 (Ga-68) PSMA PET/CT parameters that can predict patients who will respond to treatment. Methods These single-center retrospective data were obtained from metastatic CRPC patients receiving intravenous 6.0-8.5 GBq Lu-177 PSMA treatment every 6-8 weeks for a maximum of 3-8 cycles, with baseline Ga-68 PSMA PET/CT scan, clinical data, and information on treatment responses. All lesions were divided into two groups according to the increase and decrease in PSMA expression levels of 600 bone lesions and 85 lymph nodes that were compatible with metastasis of 23 patients after the treatment. The primary endpoint of our study was the evaluation of the relation between the baseline SUVmax, PSMA TV, TL PSMA values, and the treatment response of the two groups. The threshold values were determined for the parameters that had significant relations. In the present study, the prostate-specific antigen (PSA) response and treatment-induced toxicities were also evaluated as the secondary endpoint. Results It was found that SUVmax, PSMA TV, and TL PSMA values in bone metastases showed significant differences between the groups with decreased and increased PSMA expression levels after the treatment. The AUC value for SUVmax was significant (AUC = 0.677; p < 0.001). The cutoff value was > 10.50 (sensitivity = 91.8%, Specificity = 41.5%) for SUVmax, > 1.50 cm(3) (sensitivity = 49.1%, specificity = 70%) for PSMA TV and > 8.50 g (sensitivity = %60.9, specificity = %72.2) for TL PSMA. The median SUVmax value before the treatment in all metastatic lymph nodes was found to be 7.1 (5.4-12.4), and the median SUVmax after the treatment was 2.5 (1.6-12.1) (p < 0.001). Conclusion It was shown in the present study that Lu-177 PSMA treatment response may be higher in CRPC patients with metastatic bone lesion with high baseline PSMA expression level, and better treatment response may be achieved in patients with lymph node metastases than in bone metastases.