<p>This systematic review and meta-analysis evaluated the safety and efficacy of somatostatin receptor (SSTR) peptide receptor radionuclide therapy (PRRT) in patients with metastatic or progressive medullary thyroid cancer (MTC). PubMed, Scopus, and Web of Science databases were systematically searched from inception to April 22, 2025, to identify relevant clinical studies. Methodological quality was assessed via the National Institutes of Health Quality Assessment Tool. Pooled estimates of the disease control rate (DCR), overall response rate (ORR), and adverse events (AEs) following SSTR PRRT administration were calculated for both the imaging and biochemical endpoints via Stata software version 17. The analysis revealed pooled DCRs of 52% (95% CI: 43–61%) and 58% (95% CI: 46–70%) for the biochemical and imaging endpoints, respectively. The pooled ORRs were 32% (95% CI: 23–42%) for the biochemical endpoints and 17% (95% CI: 7–26%) for the imaging endpoints. Compared with [⁹⁰Y]Y-DOTATOC, [¹⁷⁷Lu]Lu-DOTATATE had a slightly greater pooled imaging DCR (64% vs. 50%) and a lower overall toxicity rate (7% vs. 24%). The biochemical DCRs were comparable (51–52%), although [¹⁷⁷Lu]Lu-DOTATATE achieved a higher biochemical ORR (37% vs. 29%). The [⁹⁰Y]Y-DOTATOC group reported relatively higher rates of gastrointestinal and hematologic toxicities, with only limited cases of high-grade events reported in three studies. [¹⁷⁷Lu]Lu-DOTATATE showed no renal toxicity, unlike [⁹⁰Y]Y-DOTATOC, which mainly caused low-grade nephrotoxicity events at a pooled rate of 6%. Overall, this meta-analysis suggests that SSTR PRRT is a promising therapeutic option for metastatic or progressive MTC, achieving reliable disease control with a favorable safety profile.</p>