Hypoxia‐inducible factor (HIF) prolyl hydroxylation inhibition (PHDi) has been shown to reduce mucosal disease severity in murine models of colitis at several levels of clinical and biochemical scoring. However, little is known about PHDi influence on systemic immune function during mucosal inflammation. Induction of TNBS colitis leads to an early pyrogenic response (fever), followed by a cryogenic response (hypothermia) due to bacteremia. We hypothesized that PHDi modulates systemic immune responses to bacteremia, associated with colitis. TNBS colitis mice, were treated with AKB‐4924, a HIF‐1 isoform‐predominant PHD inhibitor. AKB‐4924 treatment led to significantly reduced weight loss and disease activity, compared to vehicle. AKB‐4924 groups were pyrogenic, but did not become cryogenic. AKB‐4924 augmented epithelial barrier function and led to a 50‐fold reduction in serum endotoxin during colitis. AKB‐4924 modulated cytokines involved in pyrogenesis and cryogenesis, significantly reducing serum levels of IL‐1β (2‐fold), IL‐6 (17‐fold) and TNF‐α (3‐fold), while increasing IL‐10 (2‐fold). Neutrophils exhibited increased phagocytotic capacity and reduced TNF‐α expression (2‐fold) with AKB‐4924 pretreatment. Together, these results suggest that AKB‐4924 may prevent TNBS colitis induced endotoxemia on a multifactorial level, through previously unappreciated systemic mechanisms.