To determine the effects of co-ingested diphenhydramine (DPH) or oxycodone (OXY) on the absorption kinetics of simulated acetaminophen (APAP) overdose. This was an institutional review board-approved, prospective crossover study of ten healthy human volunteers ingesting 5 grams of APAP, 5 grams of APAP + 250 mg of DPH (APAP+DPH), or 5 grams of APAP + 0.5 mg/kg of OXY (APAP+OXY). Serum APAP concentrations (APAPs) were measured hourly from zero through eight hours and again at 24 hours, and basic noncompartmental pharmacokinetic parameters were compared. For APAP alone, the mean parameters were: maximum APAP concentration ([APAP]max) 71.8 μg/mL, time to peak [APAP] (tmax) 1.71 hours, and area under the receiver operating characteristic curve (AUC 0-8) 318.3 μg-hr/mL. For APAP+DPH, the mean parameters were: [APAP]max 67.6 μg/mL, tmax 1.90 hours, and AUC 0-8 297.7 μg-hr/mL. For APAP+OXY, the parameters were: [APAP] max 42.9 μg/mL, tmax 2.87 hours, and AUC0-8 232.1 μg-hr/mL. Compared with APAP alone, APAP+OXY had a 27% lower AUC, a 40% lower [APAP]max, and a 68% longer tmax. Co-ingested DPH had no significant effect on APAP absorption, except a 6% decrease in the AUC. Co-ingested OXY, but not DPH, delayed absorption of APAP. This suggests a potential role for activated charcoal administration beyond one hour postingestion after mixed ingestions that include OXY.