Tumor necrosis factor (TNF) is considered an adverse mediator of heat stroke (HS) based on clinical studies showing high serum levels. However, soluble TNF receptors (sTNFR; TNF antagonists) were higher in survivors than nonsurvivors and TNFR KO mice showed a trend towards increased mortality suggesting TNF has protective actions for recovery. We delineated TNF actions in HS by comparing thermoregulatory, metabolic and inflammatory responses between B6129F₂ (WT) and TNFR KO mice. Prior to heat exposure, TNFR KO mice showed ~0.4°C lower core temperature (T_c; radiotelemetry), ~10% lower metabolic rate (M_r; indirect calorimetry) and reduced plasma IL-1α and sIL-1RI than WT mice. KO mice selected warmer temperatures than WT mice in a gradient, but remained hypothermic. In the calorimeter, both genotypes showed a similar heating rate, but TNFR KO maintained lower T_c and M_r than WT mice for a given heat exposure duration and required ~30 min longer to reach maximum T_c (42.4°C). Plasma IL-6 increased at ~3h of recovery in both genotypes, but KO mice showed a more robust sIL-6R response. Higher sIL-6R in the KO mice was associated with delayed liver p-STAT3 protein expression and attenuated serum amyloid A3 (SAA3) gene expression suggesting the acute phase response (APR) was attenuated in these mice. Our data suggest that the absence of TNF signaling induced a regulated hypothermic state in the KO mice, TNF-IL-1 interactions may modulate T_c and M_r during homeostatic conditions, and TNF modulates the APR during HS recovery through interactions with the liver IL-6-STAT3 pathway of SAA3 regulation.