Objective: To evaluate the association between sedation–analgesia (SA) during initial 72 h and death/disability at 18 months of age in neonatal hypoxic-ischemic encephalopathy (HIE). Design: This was a secondary analysis of the NICHD therapeutic hypothermia (TH) randomized controlled trial in moderate or severe HIE. Receipt of SA and anticonvulsant medications at five time points were considered: prior to and at baseline, 24, 48, and 72 h of TH or normothermia. Disability was defined as mental developmental index <85, cerebral palsy, blindness, hearing impairment, or Gross Motor Function Classification System 2–5. Results: Of the 208 RCT participants, 38 (18%) infants had no exposure to SA or anticonvulsants at any of the five time points, 20 (10%) received SA agents only, 81 (39%) received anticonvulsants only, and 69 (33%) received both SA and anticonvulsants. SA category drugs were not administered in 57% of infants while 18% received SA at ≥3 time points; 72% infants received anticonvulsants during 72 h of intervention. At 18 months of age, disability among survivors and death/disability was more frequent in the groups receiving anticonvulsants, with (48 and 65%) or without (37 and 58%) SA, compared to groups with no exposure (14 and 34%) or SA (13 and 32%) alone. Severe HIE (aOR 3.60; 1.59–8.13), anticonvulsant receipt (aOR 2.48; 1.05–5.88), and mechanical ventilation (aOR 7.36; 3.15–17.20) were independently associated with 18-month death/disability, whereas TH (aOR 0.28; 0.13–0.60) was protective. SA exposure showed no association with outcome. Conclusions: The risk benefits of SA in HIE need further investigation.