Background: RET proto-oncogene encodes receptor tyrosine kinase. Selpercatinib was the first RET-specific tyrosine kinase inhibitor approved by FDA in RET-altered tumors (pralsetinib was approved afterward). This systematic review and meta-analysis will assess the efficacy and safety of selpercatinib in RET-altered tumors. Methods: A search was performed on PubMed, Embase, Cochrane, WOS, and clinicaltrials.gov. We used the following mesh and Emtree terms, “selpercatinib” AND “proto oncogene proteins c ret,” from the inception of literature till 10/15/2021. We screened 187 articles and included 2 phase I/II clinical trials (N = 309) in this meta-analysis. We excluded preclinical trials, case reports, case series, review articles, observational studies, meta-analysis, and clinical trials not providing any information about the efficacy of selpercatinib in RET-altered tumors. The quantitative analysis was performed using the R programming language. Results: In 2 clinical studies (N = 309), 144 patients had RET-altered advanced non-small cell lung cancer (NSCLC) and 162 had thyroid cancer. RET mutations were reported in 143 patients and RET-fusion in 163 tumors. 179 patients were previously treated with systemic therapy while 127 patients were treatment naïve. Pooled overall response (OR), complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD) were 72% (95% CI = 0.64-0.78, I²= 40%), 6% (95% CI = 0.03-0.13, I²= 49%), 66% (95% CI = 0.57-0.74, I²= 50%), 3% (95% CI = 0.01-0.06, I²= 0), and 24% (95% CI = 0.18-0.30, I²= 22%), respectively, in RET-altered thyroid/NSCLC patients. Pooled OR was 67% (95% CI = 0.60-0.73, I²= 0), 78% (95% CI = 0.64-0.87, I²= 51%), 75% (95% CI = 0.58-0.87, I²= 68%), and 71% (95% CI = 0.63-0.78, I²= 0%) in previously treated, treatment naïve, RET-fusion tumor, and RET-mutation tumor patients, respectively. Pooled incidence of ≥grade 3 any adverse event, rise in ALT, rise in AST, diarrhea, hypertension, and QT abnormalities were reported in 58% (95% CI = 0.43-0.72, I²= 85%), 10% (95% CI = 0.08-0.14, I²= 0), 11% (95% CI = 0.07-0.15, I²= 17), 5% (95% CI = 0.03-0.08, I²= 0), 17% (95% CI = 0.11-0.26, I²= 62%), and 4% (95% CI = 0.02-0.07, I²= 18%) of the participants, respectively. Conclusions: Selpercatinib was safe and effective in patients with RET-altered NSCLC and thyroid cancer regardless of prior treatment status and type of RET alteration. On indirect comparison, the safety profile with selpercatinib was better than previously used non-specific RET-inhibitors. Randomized clinical trials (RCTs) NCT04211337 and NCT04194944 are in progress to compare selpercatinib with non-specific RET inhibitors and chemotherapy/PD-1 inhibitor. More RCTs are needed to assess the combinations of selpercatinib with other drugs.