The detrimental consequences and the rise of resistance to synthetic anthelmintics necessitate the identification of innovative anthelmintics from alternative origins. This investigation emphasizes a comparative analysis of the anthelmintic efficacy and safety assessment of ethanolic bark extract (EtBE) and seed extract (EtSE) from Artocarpus chaplasha, augmented by in-silico investigations to reveal potential bioactive constituents. The anthelmintic property was evaluated by in-vitro worm motility assay on Paramphistomum cervi by monitoring paralysis and death times. Brine shrimp lethality assay (BSLA) technique was adopted to quantify cytotoxicity profile. Extensive computational analyses, encompassing ADMET, PASS prediction, molecular docking, dynamics simulation, and density functional theory (DFT) assessment were conducted utilizing phytochemicals from A. chaplasha against the beta-tubulin chain (B0RZ81) of the liver fluke. Additionally, human beta-tubulin (6QUS) and topoisomerase IIα (5GWK) proteins were investigated for the in silico cytotoxicity analysis. The worm motility assay indicated a significant dose-dependent anthelmintic effect for both herbal extracts. At a concentration of 100 mg/mL, EtBE demonstrated complete immobilization within 10.30 min and achieved 100 % mortality by 13.37 min, comparable to the effects of albendazole at the same concentration. The BSLA revealed a lower toxicological profile for the bark extract with an LC₅₀ value of 1839.68 µg/mL, in contrast to the seed extract, which exhibited an LC₅₀ value of 668.59 µg/mL. Molecular docking studies indicated that 3-(hydroxyprenyl) isoetin and 3́-farnesyl-apigenin from A. chaplasha could disrupt tubulin polymerization through interactions with vinblastine and GTP-binding sites, respectively, in the liver fluke, displaying superior binding affinities (-8.0 and −7.0 kcal/mol) compared to albendazole. Computed RMSD, RMSF, SASA, hydrogen bonding, and MM/GBSA energy assessments confirmed stable binding interactions of the compounds within the binding sites over time. Furthermore, in-silico analysis substantiated favorable pharmacokinetic characteristics (ADME) of the phytochemicals and a reduced predicted affinity for host cytotoxicity targets relative to vincristine. The cumulative evidence from both in vitro and in-silico studies affirms the significant anthelmintic efficacy and minimal cytotoxicity profile for EtBE derived from A. chaplasha. The results advocate for 3́-farnesyl-apigenin and 3-(hydroxyprenyl) isoetin to be promising anthelmintic candidates warranting further phytochemical isolation, in vivo animal trials, followed by pre-clinical assessments.