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The burden of influenza in Mexico has been high. We aimed to characterize its epidemiological patterns before and during the coronavirus disease 2019 (COVID-19) pandemic. A retrospective cohort study was conducted and 5652 PCR-confirmed cases of influenza (October 2019–April 2022) were analyzed. The highest incidence (144 per million) was observed in December 2019 and rapidly decreased right before the start of the pandemic (February 2020). No cases were documented in the 2020–2021 season, and infections reemerged at a low level (8 per million) in December 2021. The case-fatality rates were around 5% in both seasons (p = 0.591). The dominant strains were AH1N1 and AH3N2 in the 2019–2020 and 2021–2022 seasons, respectively. In multiple analysis, males and older patients were at increased risk of a fatal outcome. Flu vaccination and infection by B lineages (vs. AH1N1) showed a protective effect. Our results suggest that the spread of the influenza virus reemerged in the 2021–2022 season when the SARS-CoV-2 Omicron variant (B.1.1.529) was dominant. Efforts focusing on the prevention of transmission of respiratory viral pathogens, together with flu vaccination, may be useful to reduce the risk of an influenza outbreak.