This study leverages electronic health record data in the National COVID Cohort Collaborative’s (N3C) repository to investigate disparities in Paxlovid treatment and to emulate a target trial assessing its effectiveness in reducing COVID-19 hospitalization rates. From an eligible population of 632,822 COVID-19 patients seen at 33 clinical sites across the United States between December 23, 2021 and December 31, 2022, patients were matched across observed treatment groups, yielding an analytical sample of 410,642 patients. We estimate a 65% reduced odds of hospitalization among Paxlovid-treated patients within a 28-day follow-up period, and this effect did not vary by patient vaccination status. Notably, we observe disparities in Paxlovid treatment, with lower rates among Black and Hispanic or Latino patients, and within socially vulnerable communities. Ours is the largest study of Paxlovid’s real-world effectiveness to date, and our primary findings are consistent with previous randomized control trials and real-world studies.