Background To compare the antipyretic effect of simultaneously administered acetaminophen (APAP) plus ibuprofen (IBU) to either APAP or IBU alone in critically ill febrile neurological and neurosurgical patients. Methods This is a prospective, three-armed, randomized controlled trial of 79 patients in the neurology/neurosurgery intensive care unit (NNICU) of a tertiary care academic hospital. Eligible patients who developed a temperature ≥38°C were randomized to receive either a single dose of APAP 975 mg, a single dose of IBU 800 mg, or a combination of both (APAP + IBU). Oral temperatures were measured hourly for 6 h following medication administration. Results All three treatments decreased temperature over the 6-h period. The area under the curve (AUC) for ΔT for APAP was -3.55°C-h (95% CI -4.75 to -2.34°C-h); for IBU was -4.05°C-h (95% CI -5.16 to -2.94°C-h); and for the combination of APAP and IBU was -5.10°C-h (95% CI -6.20 to -4.01°C-h). The differences in AUC between the groups were as follows: IBU versus APAP = -0.50°C-h (P = 0.28), APAP + IBU versus IBU = -1.05°C-h (P = 0.09), and APAP + IBU versus APAP = -1.56°C-h (P = 0.03). Conclusion The combination of IBU and APAP produces significantly greater fever control than APAP alone, with trends favoring the combination over IBU alone and IBU over APAP alone.