Most influenza vaccines in Mexico are trivalent, containing two influenza A strains and a single B strain. Quadrivalent influenza vaccines (QIVs) extend protection by including an additional B strain to cover both co-circulating B lineages. Here, we retrospectively estimated how a switch to QIV in Mexico would have impacted influenza-related health outcomes over the 2010/2011 to 2015/2016 influenza seasons, and prospectively estimated the budget impact of using QIV in Mexico’s national immunization program from 2016/2017 to 2020/2021. For the retrospective estimation, we used an age-stratified static model incorporating Mexico-specific input parameters. For the prospective estimation, we used a budget impact model based on retrospective attack rates considering predicted future vaccination coverage. Between 2010/2011 and 2015/2016, a switch to QIV would have prevented 270,596 additional influenza cases, 102,000 general practitioner consultations, 140,062 days of absenteeism, 3,323 hospitalizations, and 312 deaths, saving Mex$214 million (US$10.8 million) in third-party payer costs. In the prospective analysis, a switch to QIV was estimated to prevent an additional 225,497 influenza cases, 85,000 general practitioner consultations, 116,718 days of absenteeism, 2,769 hospitalizations, and 260 deaths, saving Mex$178 million (US$9 million) in third-party payer costs over 5 years. Compared to the trivalent vaccine, the benefit and costs saved with QIV were sensitive to the distribution of influenza A vs. B cases and trivalent vaccine effectiveness against the mismatched B strain. These results suggest switching to QIV in Mexico would benefit healthcare providers and society by preventing influenza cases, morbidity, and deaths, and reducing associated use of medical resources.