<p>Alternative administrations methods, such as chewing or crushing tablets, have been proposed to improve P2Y₁₂ receptor inhibitors’ absorption in acute and chronic coronary syndromes. This study aimed to evaluate the impact of these alternative strategies on the pharmacokinetics and pharmacodynamics of clopidogrel, ticagrelor, and prasugrel. PubMed, the Cochrane Library, and Web of Science were searched until March 07, 2025 for trials comparing at least one P2Y₁₂ receptor inhibitor alternative administration method to the standard administration (swallowed integral tablets). Drug concentrations, platelet reactivity, and rates of high on-treatment platelet reactivity (HPR) were evaluated by standardized mean differences (SMD) or odds ratios (OR) with 95% confidence interval (CI) using random-effects models. The effects of specific P2Y₁₂ inhibitors and administration methods were assessed using meta-regression. Eleven studies (1,735 patients) were included. Administration of crushed or chewed tablets led to an increase in drug concentrations (SMD at 1 h 0.48, 95% CI 0.001 to 0.95, p &lt; 0.05), resulting in a significant improvement in platelet inhibition (SMD at 1 h -0.53, 95% CI -0.67 to -0.39, p &lt; 0.001) and a reduction in HPR rates (OR 0.29, 95% CI 0.16 to 0.54, p &lt; 0.001) as early as 30&#xa0;min and during the first 4&#xa0;h after administration. No differences were found between prasugrel and ticagrelor or between crushed and chewed tablets in the pharmacodynamic outcomes, providing flexibility in clinical practice. Further research is needed to confirm the clinical relevance of these findings.</p>