Background: Endometrial cancer (EC) is the second most prevalent gynecological cancer. After failure to first-line platinum-based chemotherapy, treatment options are sparse, but recent studies have investigated new approaches with promising results. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Lenvatinib plus Pembrolizumab in patients with advanced or recurrent EC. Methods: PubMed, Web of Science, Cochrane, Scopus, and LILACS databases, Central Register of Clinical Trials, and congresses publication websites were searched for studies using Lenvatinib plus Pembrolizumab in advanced or recurrent EC with progression after platinum-based chemotherapy. Outcomes of interest were best overall response rate (BORR) and disease control rate (DCR), on intention-to-treat (ITT) and per-protocol analyses, and according to mismatch repair status. Progression free-survival (PFS) and overall survival (OS) were also assessed. Heterogeneity was examined with the Cochran Q test and I² statistics. We use a DerSimonian and Laird random-effects model. Results: Four studies, with 637 patients, were included: two clinical trials and two retrospective observational cohorts. Endometrioid EC was the predominant histology (53%), and most patients had mismatch repair-proficient tumors (pMMR, 86.5%). In a pooled analysis, with a medium follow-up of 12.2 months, BORR was 31% (95%CI 26, 37), and DCR was 74% (95%CI 65, 83) on ITT. CR, PR, and SD were documented in 37 (5.8%),168 (26.3%) and 284 (44.5%) patients, respectively. BORR was 48% in microsatellite unstable tumors compared to 31% in stable microsatellite disease (p = 0.07), while DCR was similar in both groups (p = 0.33). Median progression-free survival was 7.2 months (95%CI 3.2, 7.4), and median overall survival was 18.3 months (95%CI 8.6, 18.3) in patients receiving Lenvatinib and Pembrolizumab. The most common treatment-related adverse events (AE) included diarrhea 277/514 (53.8%), nausea 244/514 (47.4%), hypothyroidism 288/562 (39.1%), hypertension 338/632 (36.9%), fatigue 213/632 (31.0%), and vomiting 178/514 (34.6%). Grades 3 or 4 AE was reported in 436/514 (79.6%) patients. Overall, dose reductions, treatment interruptions, and discontinuation due to toxicities were required in 61%, 63%, and 27% of patients, respectively. Conclusions: This systematic review and meta-analysis reinforce the antitumor activity of the combination of Pembrolizumab and Lenvatinib in patients with advanced or recurrent EC, regardless of MMR status. Despite high rates of serious adverse events related to treatment, most were manageable.