Background: With the publication of a large number of clinical studies on antiplatelet therapy in recent years, it is still controversial which antiplatelet monotherapy should be continued after a period of dual antiplatelet therapy (DAPT) in the post percutaneous coronary intervention (post-PCI) population. We conducted a meta-analysis to investigate the efficacy and safety of P2Y{}_{12} inhibitors versus aspirin in the post-PCI population after completing DAPT. Methods: We searched studies in electronic databases from January 1, 2015 to November 20, 2022. We conducted a meta-analysis to estimate the effect of P2Y{}_{12} inhibitor monotherapy on clinical end-points in post-PCI patients after a period of DAPT, using trial-level data with consistent end-point definitions. The primary outcome was major adverse cardiovascular events (MACE). Odd ratio (OR) was pooled with 95% confidence interval (CI) for dichotomous data. This study is registered with INPLASY 2022120011. Results: We included five studies that included 24,460 patients. The patients who received a P2Y{}_{12} inhibitor showed a lower risk of MACE than patients who received aspirin (OR 0.70 [95% CI 0.60–0.80], I{}^2 = 0%, p 0.00001) monotherapy. Subgroup analysis of MACE based on patient characteristics showed consistent results with the main analysis. The risk of major bleeding was similar in patients who received a P2Y{}_{12} inhibitor and those who received aspirin (OR 0.86 [95% CI 0.53–1.39], I{}^2 = 57%, p = 0.54). The risk of major bleeding was borderline increased in patients who received ticagrelor versus aspirin (OR 1.81 [95% CI 0.99–3.31], p = 0.05). Conclusions: In the post-PCI population, P2Y{}_{12} inhibitor monotherapy may be superior to aspirin for MACE, repeat revascularization, and stroke without increasing the risk of major bleeding.