The nonstructural protein 3 (Nsp3) of SARS-CoV-2 is a large, multi-domain protein that localizes to double-membrane vesicles (DMVs), the physical site where SARS-CoV-2 (and other coronaviruses) replicate inside mammalian cells. One of the domains of Nsp3 is PLpro (papain-like protease), which harbors enzymatic activities (i.e., protease, deubiquitinase, and deISGylase). To identify human cellular proteins that bind Nsp3, we performed LC-MS/MS analysis of affinity-purified Nsp3 from SARS‑CoV‑2–infected Caco-2 (human intestinal epithelial) cells. This dataset identified numerous Nsp3-interacting proteins that play key roles in various host cellular processes, including metabolism and innate immunity.