The study investigated the growth-inhibiting and apoptosis mediating effects of B. serrata extract as monotherapy and combination therapy with DOX against hepatocellular carcinoma cell lines. Boswellic acid rich fraction of B. serrata extract was prepared. MTT assay on HepG2 and Hep3B cells was carried out using B. serrata alone and in combination with DOX. Further, caspase-3 activity, TNF-α level, and IL-6 level were estimated. Isobolographic analysis was carried out to evaluate the effect of combination therapy. Additionally, protective effect of B. serrata extract on DOX induced hepatic toxicity was also evaluated in Wistar rats. B. serrata extract inhibited growth of HepG2 (IC50 value of 21.21 ± 0.92 μg/mL) as well as HepG2 (IC50 value of 18.65 ± 0.71 μg/mL). DOX inhibited growth in HepG2 and Hep3B cells with an IC50 of 1.06 ± 0.04 μg/mL and 1.92 ± 0.09 μg/mL. Isobolographic analysis showed combination index (CI) of DOX and B. serrata extract of 0.53 ± 0.03 to 0.79 ± 0.02 suggesting synergistic behavior against the two cell lines. B. serrata extract also caused dose dependent increase in caspase-3 activity, TNF-α level, and IL-6 level which was higher (P < 0.001) with DOX (1 μM) and B. serrata extract (20 μg/mL) combination. B. serrata extract also protected Wistar rats against DOX induced hepatic toxicity.