Purpose <p>This systematic review and meta-analysis evaluates xerostomia occurrence in prostate cancer (PC) patients undergoing [²²⁵Ac]Ac-prostate-specific membrane antigen ([²²⁵Ac]Ac-PSMA) therapy.</p> Methods <p>Following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines, comprehensive electronic searches were conducted across PubMed, Scopus, and Web of Science. The study included articles addressing xerostomia as a side effect of [²²⁵Ac]Ac-PSMA therapy in clinical settings, encompassing both tandem and monotherapy strategies. Methodological quality was assessed using the National Institutes of Health (NIH) Assessment Tool. Stata software was employed to perform pooled xerostomia rates, heterogeneity analysis, meta-regression, and publication bias analysis.</p> Results <p>Twenty studies met inclusion criteria, comprising 2949 [²²⁵Ac]Ac-PSMA cycles administered to 1207 PC patients. For [²²⁵Ac]Ac-PSMA monotherapy, the pooled rate of any-grade xerostomia was 84% (95%CI: 69–94%). Grade 1–2 xerostomia had a pooled rate 83% (95%CI: 71–93%), while therapy discontinuation due to xerostomia was 5% (95%CI: 0–13%). Grade 3 xerostomia was evident in 13% (95%CI: 7–20%). [²²⁵Ac]Ac/[¹⁷⁷Lu]Lu-PSMA tandem therapy resulted in lower pooled rate of 68% for grade 1–2 toxicity (95%CI: 17–100%). Indirect comparison revealed a two-fold decrease in xerostomia risk with tandem protocol compared to monotherapy. Significant heterogeneity was observed, primarily influenced by baseline median prostate-specific antigen values (<i>p</i> = 0.04). Publication bias was present in most xerostomia subgroups, with trim-and-fill analysis adjusting for effect size in specific categories.</p> Conclusion <p>Xerostomia is most pronounced in patients undergoing [²²⁵Ac]Ac-PSMA monotherapy. Tandem approach with [¹⁷⁷Lu]Lu-PSMA could reduce xerostomia rates and improve compliance. Further large-scale, prospective studies are necessary for generalization and result consolidation.</p>