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Most Prostate Specific Membrane Antigens (PSMAs) targeting small molecules accumulate in the salivary glands (SGs), raising concerns about SG toxicity, especially after repeated therapies or therapy with ²²⁵Ac-labeled ligands. SG toxicity is assessed clinically by the severity of patient-reported xerostomia, but this parameter can be challenging to objectively quantify. Therefore, we explored the feasibility of using SG volume as a biomarker for toxicity. In 21 patients with late-stage metastatic resistant prostate cancer (mCRPC), the PSMA volume and ligand uptake of SG were analyzed retrospectively before and after two cycles of ¹⁷⁷Lu-PSMA (LuPSMA; cohort A) and before and after one cycle of ²²⁵Ac-PSMA-617 (AcPSMA, cohort B). Mean Volume-SG in cohort A was 59 ± 13 vs. 54 ± 16 mL (−10%, p = 0.4), and in cohort B, it was 50 ± 13 vs. 40 ± 11 mL (−20%, p = 0.007), respectively. A statistically significant decrease in the activity concentration in the SG was only observed in group B (SUV_mean: 9.2 ± 2.8 vs. 5.3 ± 1.8, p < 0.0001; vs. A: SUV_mean: 11.2 ± 3.3 vs. 11.1 ± 3.5, p = 0.8). SG volume and PSMA-ligand uptake are promising markers to monitor the SG toxicity after a PSMA RLT.