The availability of 20-h N-acetylcysteine (NAC) infusion for low-risk acetaminophen (APAP) overdose enabled our center to implement an Emergency Department observation unit (OU) protocol as an alternative to hospitalization. Our objective was to evaluate our early experience with this protocol. This retrospective cohort study included all patients treated for low-risk APAP overdose in our academic hospital between 2006 and 2011. Cases were identified using OU and pharmacy records. Successful OU discharge was defined as disposition with no inpatient admission. Differences in medians with 95 % confidence intervals were used for comparisons. One hundred ninety-six patients received NAC for APAP overdose with a mean age of 35 years (SD 14); 73 % were white, and 43 % were male. Twenty (10 %) received care in the OU; 3/20(15 %) met criteria for inclusion in the OU protocol and 13/20(65 %) were discharged successfully. Out of the 196 patients, 10 met criteria for inclusion in the OU protocol but instead received care in the inpatient setting. The median total length of stay from presentation to ED discharge was 41 h for all patients treated in the OU, compared to 68 h for ten patients who met criteria for inclusion in the OU protocol but who were admitted (difference 27 h, 95 % CI 18–72 h). ED observation for APAP overdose can be a viable alternative to inpatient admission. Most patients were successfully discharged from the OU. This evaluation identified both over- and under-utilization of the OU. OU treatment resulted in shorter median length of stay than inpatient admission.