Toll‐like receptors (TLRs) lie in the core of resistance to infectious diseases allowing host immune cells to specifically detect pathogens by recognising their specific molecular patterns. Cell membrane‐associated TLR4 (recognises lipopolysaccharide (LPS) of Gram‐negative bacteria) and endosomal TLR7/8 (recognise viral single‐stranded RNA) are known to activate hypoxia inducible factor‐1α (HIF‐1α) protein (necessary for cellular adaptation to the inflammatory stress) via redox‐dependent mechanism. TLR4 triggers the cross talk between HIF‐1α and apoptosis signal‐regulating kinase 1 (ASK1), whereas TLR7/8 activates HIF‐1α in the ASK1‐independent manner. Here, we report that in THP‐1 and RAW264.7 macrophages, ligand‐induced activation of the TLR4 but not TLR7/8 induces activation and transcriptional upregulation of sphingosine kinase 1 (SphK1) in extracellular signal‐regulating kinase and phospholipase C‐1γ/PI3 kinase‐dependent manner. TLR4‐mediated SphK1 activation was found to be critical for the redox‐dependent activation of HIF‐1α and ASK1, as well as for the prevention of LPS‐induced activation of caspase 3 and the expression of pro‐inflammatory cytokine interleukin‐6.