Background: Unicompartmental knee arthroplasty (UKA) and high tibial osteotomy (HTO) are widely used for the treatment of medial unicompartmental knee osteoarthritis (OA). However, the best approach remains controversial. This study aimed to present a systematic review and a meta-analysis to directly compare the clinical outcomes between HTO and UKA. We hypothesized that the clinical outcomes after UKA and HTO would be similar. Methods: Electronic databases (Web of Science, PubMed, Embase, CENTRAL, and Biosis Preview) were searched for related studies published before November 30, 2021. Retrospective and prospective studies that directly compared the postoperative outcomes between UKA and HTO were included. Odds ratio (ORs) and 95% confidence interval (CIs) for complications, revision to total knee arthroplasty (TKA), and weighted mean difference (MD) and 95% CIs in range of motion (ROM), pain, walking speed and function score were evaluated. Two reviewers independently assessed the quality of the studies. Subgroup and sensitivity analyses were performed to explore the heterogeneity. Results: Twenty-three retrospective and 6 prospective studies were included. A total of 3004 patients (3084 knees) were evaluated for comparison. Complications (OR, 4.88, 95% CI: 2.92–6.86) were significantly greater in the HTO group than in the UKA group. Postoperative function scores including Lysholm score (MD, −2.78, 95% CI: −5.37 to −0.18) and Hospital for Special Surgery (HSS) score (MD, −2.80, 95% CI: −5.39 to −0.20) were significantly lower in the HTO group than the UKA group. The postoperative ROM was similar between HTO and mobile-bearing UKA (MD, −3.78, 95% CI: −15.78 to 8.22). However, no significant differences were observed between the HTO and UKA group in terms of postoperative pain, walking speed, and revision to TKA. Conclusions: UKA is superior to HTO in minimizing complications and enhancing postoperative function scores. Mobile-bearing UKA has a similar ROM compared with HTO. Both HTO and UKA provide satisfactory clinical outcomes in terms of walking speed, relieving pain, and revision to TKA. UKA appears to be more suitable for the elderly, and both mobile-bearing UKA and HTO are viable surgical options for younger active individuals.