The introduction of a pneumococcal conjugate vaccine (PCV) covering 13 serotypes (PCV13) into the Mexican pediatric national immunization program (NIP) has substantially reduced the burden of pneumococcal disease (PD) since 2010. This study aimed to estimate the impact of replacing either PCV13 or 15valent PCV (PCV15) with 20-valent PCV (PCV20) in the Mexican pediatric NIP. A decision-analytic Markov model was developed to compare the cost-effectiveness of PCV20 versus lower-valent vaccines from a Mexican public health sector (payer) perspective over 10 years. Epidemiological and cost inputs were sourced from Mexican data. Direct and indirect vaccine effects were estimated using PCV13 clinical effectiveness, 7-valent PCV efficacy studies, and PCV13 impact data in Mexico. The estimated disease and cost impact of PCV20 was compared with PCV13 and PCV15, all under a 2 + 1 dosing schedule. A discount rate of 5% per annum was applied to costs and health outcomes. Model robustness was evaluated through sensitivity analyses, including deterministic sensitivity analysis (DSA), probabilistic sensitivity analysis (PSA), and additional scenario assessments. PCV20 was estimated to provide considerably more health benefits than both comparators by averting more cases of PD compared with both PCV13 and PCV15, as well as a total cost saving of over 10 billion Mexican pesos. The DSA, PSA, and scenario assessments confirmed minimal deviation from the base case. Therefore, the introduction of PCV20 (2 + 1) into the Mexican pediatric NIP is expected to reduce the burden of PD and medical costs compared with lower-valent alternatives.