Pneumococcal conjugate vaccines (PCVs) have been used in the United States since 2000. To assess the cumulative 20-year effect of PCVs on invasive pneumococcal disease (IPD) incidence among children <5 years of age, we analyzed Active Bacterial Core Surveillance data, conducted a literature review, and modeled expected and observed disease. We found that PCVs have averted >282,000 cases of IPD, including ≈16,000 meningitis, ≈172,000 bacteremia, and ≈55,000 bacteremic pneumonia cases. In addition, vaccination has prevented 97 million healthcare visits for otitis media, 438,914–706,345 hospitalizations for pneumonia, and 2,780 total deaths. IPD cases declined 91%, from 15,707 in 1997 to 1,382 in 2019. Average annual visits for otitis media declined 41%, from 78 visits/100 children before PCV introduction to 46 visits/100 children after PCV13 introduction. Annual pneumonia hospitalizations declined 66%–79%, from 110,000–175,000 in 1997 to 37,000 in 2019. These findings confirm the substantial benefits of PCVs for preventing IPD in children.