Background: In Australia, 2017 was a severe A/H3N2 season and, therefore, we estimated the effectiveness of standard-dose quadrivalent influenza vaccine in preventing hospitalization for cardiovascular disease (CVD) among New South Wales (NSW) residents aged ≥50 years. Methods: We conducted a nested, matched case–control study within the 45 and Up study, linking data from the Australian Immunization Register, NSW Admitted Patient Data Collection and Pharmaceutical Benefits Schedule. Cases were individuals hospitalized for CVD and controls were those who were hospitalized for gastrointestinal diseases. The two groups were balanced using 1:1 propensity score matching based on age group (50–64, 65–74, 75–84, and ≥85 years) and sex. After adjusting for confounders (smoking, body mass index and income), we calculated the adjusted odds ratio (aOR) for vaccination during the season using multivariable logistic regression. E-values were estimated to assess residual confounding. Vaccine effectiveness (VE) was calculated as (1 ? aOR) × 100. Results: There were 10,445 (4452 cases and 5993 controls) study participants. After matching, 8904 (85.2%) were retained with a mean age of 76.4 ± 10.4 years and 58.3% men. Following adjustment for confounders, the aOR of averting a CVD hospitalization was 0.15 (95% CI: 0.13 to 0.17; p < 0.001). The estimated VE against CVD hospitalization was 85% (95% CI: 83 to 87). We found an E-value of 12.82, indicating strong evidence of minimal residual confounding. Conclusions: In the severe 2017 influenza A/H3N2 season in Australia, we observed a high VE in preventing cardiovascular hospitalization despite a low VE against influenza infection prevention. Improving vaccine uptake may reduce cardiovascular burden.