Crocetin is a main bioactive component with a carotenoid skeleton in Gardenia jasminoides, a typical traditional Chinese medicine with a long history in Southeast Asia. Crocetin is being commonly consumed as spices, dyes, and food colorants. Recent pharmacological studies had implied that crocetin may possess potent anti‐inflammatory properties; however, the underlying molecular mechanism is not fully elucidated. In the present study, the regulatory effect of crocetin on redox balance was systematically investigated in lipopolysaccharide‐ (LPS‐) stimulated RAW264.7 cells. The results showed that crocetin dose‐dependently inhibited LPS‐induced nitric oxide production and inducible nitric oxide synthase (iNOS) expression in RAW264.7 cells. Molecular data revealed that crocetin exerted its anti‐inflammatory property by inhibiting the MEK1/JNK/NF‐κB/iNOS pathway and activating the Nrf2/HO‐1 pathway. The shRNA‐knockdown (KD) of MEK1 and ERK1 confirmed that the activation of MEK1 and inhibition of JNK mediated the anti‐inflammatory effect of crocetin. Moreover, the pull‐down assay and computational molecule docking showed that crocetin could directly bind to MEK1 and JNK1/2. It is noticed that both KD and knockout (KO) of HO-1 gene blocked this action. More detailed data have shown that HO-1‐KO blocked the inhibition of p‐IκB‐α by crocetin. These data indicated that crocetin exerted its anti‐inflammatory property via modulating the crosstalk between the MEK1/JNK/NF‐κB/iNOS pathway and the Nrf2/HO‐1 pathway, highlighting HO‐1 as a major player. Therefore, the present study reveals that crocetin can act as a potential candidate for redox‐balancing modulation in charge of its anti‐inflammatory and chemopreventive effect, which strengthens its potency in the subsequent clinic application in the near future.