•Seasonal influenza viruses typically circulate in South America from April-November.•Among those vaccinated in 2022, the odds of influenza hospitalization were 1/3 lower.•Vaccine effectiveness was higher in the early season than in the late season.•Health officials should encourage communities to seek influenza vaccination. This study estimated the 2022 end-of-season influenza vaccine effectiveness (VE) against severe acute respiratory illness (SARI) hospitalization in Chile, Paraguay, and Uruguay. We pooled surveillance data from SARI cases in 18 sentinel surveillance hospitals in Chile (n = 9), Paraguay (n = 2), and Uruguay (n = 7) from March 16-November 30, 2022. VE was estimated using a test-negative design and logistic regression models adjusted for country, age, sex, presence of ≥1 comorbidity, and week of illness onset. VE estimates were stratified by influenza virus type and subtype (when available) and influenza vaccine target population, categorized as children, individuals with comorbidities, and older adults, defined per countries’ national immunization policies. Among the 3147 SARI cases, there were 382 (12.1%) influenza test-positive case patients; 328 (85.9%) influenza case patients were in Chile, 33 (8.6%) were in Paraguay, and 21 (5.5%) were in Uruguay. In all countries, the predominant subtype was influenza A(H3N2) (92.6% of influenza cases). Adjusted VE against any influenza-associated SARI hospitalization was 33.8% (95% confidence interval: 15.3%, 48.2%); VE against influenza A(H3N2)-associated SARI hospitalization was 30.4% (95% confidence interval: 10.1%, 46.0%). VE estimates were similar across target populations. During the 2022 influenza season, influenza vaccination reduced the odds of hospitalization among those vaccinated by one-third. Health officials should encourage influenza vaccination in accordance with national recommendations.