The SARS-CoV-2 pandemic challenged health systems worldwide. In Mexico, the Public Health Incident Management Command (COISS) strategy was implemented to improve health care for patients with COVID-19 who required hospitalization. To evaluate the impact of the COISS strategy on case fatality rates (CFR) and years of life lost (YLL) in hospitalized patients with COVID-19. The COISS strategy included eight actions implemented in states with high epidemic risk (COISS states). A secondary analysis of the public database from the Mexican Ministry of Health was performed considering patients with confirmed diagnoses of SARS-CoV-2 infection. The COISS strategy effectiveness was evaluated by its impact on in-hospital CFR and YLL at the beginning (T0) and end (T1) of the third wave, and at the end of the fourth wave (T2) and compared to states without intervention (non-COISS states). At T0, COISS states showed a higher CFR for hospitalized patients than non-COISS states, which decreased after the strategy implementation. After correction for baseline conditions, lower relative CFR at T1 and T2, compared to T0, and a protective effect in different age groups, especially in those ≥65 years, were found in hospitalized patients in COISS states. The COISS strategy was associated with lower CFR in hospitalized patients with COVID-19 at both T1 and T2. At T0, YLLs were higher in COISS states, but there were no significant differences at T1 and T2. COISS interventions effectively reduced CFR in hospitalized patients with COVID-19, providing protection to vulnerable patients and reducing the YLL gap.