Smoking has been associated with NAFLD recently, thus might be a contributing factor for liver disease progression. In this study, we identified the modulative action of α-lipoic acid (α-LA), an organosulphur compound, towards heated tobacco product (HTP) and cigarette smoke extract (CSE)-induced oxidative stress and inflammation in human liver HepG2 cells. The cells were pre-treated with α-LA and exposed to tobacco extracts, and cytotoxicity, oxidative response (SOD, CAT activities and GSH, MDA levels), inflammation (nitrite, IL-6, AhR levels), and liver function (AST/ALT) were assessed. According to the results, a notable increase in oxidative response was observed with CSE, whereas GSH depletion and decreased SOD activity were the key toxicological events induced by HTP (p < 0.05). The oxidative and inflammatory responses were ameliorated with α-LA treatment, particularly through GSH restoration and IL-6 modulation. To conclude, these findings on α-LA might contribute to the design of novel adjuvant therapies for people exposed to tobacco smoke.