Purpose: To evaluate the use of topical tacrolimus as an adjunct therapy to corticosteroids in preventing graft rejection in high-risk penetrating keratoplasty (PKP). Methods: A comprehensive search was conducted through PubMed®, EMBASE®, Cochrane Central Register of Controlled Trials, and Google Scholar® databases from 2000 to 2023. Eligible studies included meta-analysis, systematic review, clinical trial, and case presentations that compared graft rejection rates in high-risk PKP patients treated with corticosteroid versus corticosteroid plus tacrolimus. Studies with a control group using noncorticosteroid therapy were excluded from the study. The study selection process followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Study quality was assessed using Cochrane Risk of Bias 2.0 (RoB 2.0), Newcastle–Ottawa Scale, and RoB for Nonrandomized Intervention Studies. Results: Five studies comprising 298 eyes were included in the study. Rejection rates were found significantly lower in the tacrolimus group (RR: 0.63; 95% confidence interval [CI]: 0.46–0.88; P = 0.006). Tacrolimus also significantly reduced irreversible rejection (RR: 0.50; 95% CI: 0.27–0.93; P = 0.03) and improved visual acuity (RR: 1.45; 95% CI: 1.08–1.93; P = 0.01). Conclusions: Tacrolimus successfully reduces the rejection rate and irreversible rejection in high-risk PKP patients. Improved visual acuity was observed. There were no significant side effects; however, further studies are still needed to achieve more quantitative results, like recommended concentrations. © 2026 Journal of Current Ophthalmology.