Clerodendrum viscosum Vent. is a well-known plant in Indian and Chinese traditional medicine systems. While studies showed its crude leaf extract's cytotoxicity against HT-29 and HeLa cells, various non-bioactive compounds present in crude extracts may influence overall bioactivity. This study aimed to separate the most bioactive fractions from Clerodendrum viscosum’s crude extracts that exhibit anticancer potential against HepG2 cells. Crude extracts were fractionated using a solvent-polarity-based process and their anticancer activity was investigated through in vitro, in silico, and network pharmacology approaches. Nonpolar leaf (CVLH) and root (CVRH) fractions showed maximum cytotoxicity in HepG2 cells without affecting noncancer-origin WRL68 cells. Both extracts induced oxidative stress, DNA damage, cell cycle arrest, and apoptosis in HepG2 cells, with CVRH exhibiting a superior effect. GC-MS analysis identified various anticancer phytochemicals differentially present in CVLH and CVRH. Network pharmacology with these phytochemicals predicted Bcl-2 as the primary target, while molecular docking confirmed lupeol, stigmasterol, alpha-amyrin, cycloartenol, and calysterol being the top five phytochemicals exhibiting strong binding against Bcl-2, androgen receptor (AR), and epidermal growth factor receptor (EGFR). Western blot confirmed an elevated Bax/Bcl-2 ratio in HepG2 cells by CVLH and CVRH. In summary, the nonpolar fractions of Clerodendrum viscosum leaf and root crude extracts showed enhanced anticancer activity, suggesting their potential pharmaceutical applications.