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Tumor necrosis factor-α (TNF-α)-induced keratinocyte inflammation plays a key role in the pathogenesis of multiple inflammatory skin diseases. Here we investigated the anti-inflammatory effect of S-allyl cysteine (SAC) on TNF-α-induced HaCaT keratinocyte cells and the mechanism behind its anti-inflammatory potential. SAC was found to inhibit TNF-α-stimulated cytokine expression. Further, SAC was found to inhibit TNF-α-induced activation of p38, JNK and NF-κB pathways. Interestingly, SAC was found to differentially regulate ERK MAP kinase in cells. TNF-α-induced transient ERK activation and SAC treatment resulted in sustained ERK activation both in the presence and absence of TNF-α. Additionally, SAC failed to inhibit the TNF-α-induced expression of the pro-inflammatory cytokines TNF-α and IL-1β when cells were treated with the MEK inhibitor PD98059, suggesting that the anti-inflammatory effect of SAC is via sustained activation of the ERK pathway. Since ERK activation has been reported to negatively regulate NF-κB-driven gene expression and we find that SAC activates ERK and negatively regulates NF-κB, we investigated whether there existed any crosstalk between the ERK and the NF-κB pathways. NF-κB-dependent reporter assay, visualization of the nuclear translocation of NF-κB-p65 subunit and determination of the cellular levels of I-κB, the inhibitor of NF-κB, revealed that SAC inhibited TNF-α-induced NF-κB activation, and PD98059 treatment reversed this effect. These results collectively suggest that SAC inhibits TNF-α-induced inflammation in HaCaT cells via a combined effect entailing the inhibition of the p38 and the JNK pathways and NF-κB pathway via the sustained activation of ERK., (© 2019 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)