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Abstract Inappropriate and chronic activation of the cytosolic NOD‐, LRR‐, and pyrin domain‐containing 3 (NLRP3) inflammasome, a key component of innate immunity, likely underlies several inflammatory diseases, including coronary artery disease. This first‐in‐human phase I trial evaluated safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of oral, single (150–1800 mg) and multiple (300 or 900 mg twice daily for 7 days) ascending doses (SADs and MADs) of GDC‐2394, a small‐molecule inhibitor of NLRP3, versus placebo in healthy volunteers. The study also assessed the food effect on GDC‐2394 and its CYP3A4 induction potential in food‐effect (FE) and drug–drug interaction (DDI) stages, respectively. Although GDC‐2394 was adequately tolerated in the SAD, MAD, and FE cohorts, two participants in the DDI stage experienced grade 4 drug‐induced liver injury (DILI) deemed related to treatment, but unrelated to a PK drug interaction, leading to halting of the trial. Both participants experiencing severe DILI recovered within 3 months. Oral GDC‐2394 was rapidly absorbed; exposure increased in an approximately dose‐proportional manner with low‐to‐moderate intersubject variability. The mean terminal half‐life ranged from 4.1 to 8.6 h. Minimal accumulation was observed with multiple dosing. A high‐fat meal led to delays in time to maximum concentration and minor decreases in total exposure and maximum plasma concentration. GDC‐2394 had minimal CYP3A4 induction potential with the sensitive CYP3A4 substrate, midazolam. Exploratory ex vivo whole‐blood stimulation assays showed rapid, reversible, and near‐complete inhibition of the selected PD biomarkers, IL‐1β and IL‐18, across all tested doses. Despite favorable PK and target engagement PD, the GDC‐2394 safety profile precludes its further development.