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This study characterized the phytochemical constituents and multi-faceted bioactivity of propolis from East Kalimantan using UPLC-MS/MS, in vitro assays, gene-expression analysis, and in silico docking with ADMET predictions. Fifteen secondary metabolites were identified with predominantly phenolic acids, flavonoids, and prenylated chromans with some of them firstly reported. The extract displayed high total phenolic content (217.3 mg GAE/g), total flavonoid content (45.8 mg QE/g) and dose-dependent antioxidant activity (DPPH IC₅₀ = 227.1 µg/mL). In HepG2 cells, the crude extract exerted moderate selective cytotoxicity (MTT IC₅₀=32.6 µg/mL) and dose-dependent transcriptional effects: AKR1C3 was downregulated at low dose but upregulated at high dose, MAPK/ERK was suppressed at both doses, and NF-κB was mildly reduced. Molecular docking indicated that key constituents (kushenol B, sophoranodichromane D, kuwanon T) bind liver-relevant targets of glutathione reductase, AST/ALT, and HCV NS3/4A with favorable poses overlapping native ligands. In silico ADMET profiling largely met Lipinski rules of five, predicted good intestinal absorption, limited CNS exposure, and few hepatotoxicity alerts, though some compounds require further toxicity evaluation. Together, these results position propolis as a phenolic-rich source of multi-target hepatoprotective and chemopreventive candidates, meriting in vivo validation and detailed ADME/toxicity studies.