• Metabolite screening was achieved by using standard qualitative tests. • Bioactive metabolites were separated and identified by De-replication approach, coupling HPLC-ESI-QTOF-MS with MZmine 3, global natural products social molecular networking (GNPS) and METLIN Gen2. • Microwave digestion was used to extract metals for inductively coupled plasma optical emission spectroscopy (ICP-OES) analysis. • Health risk assessment was achieved by determining estimated daily intake (EDI), hazard quotients (HQ), and carcinogenic risk (CR). The bark of Entandrophragma delevoyi De Wild (E. delevoyi) is widely used in the Zambian traditional health care system as a very effective medicinal plant. Nevertheless, little is known about the phytochemicals affiliated with the ethno-pharmacological uses of the plant. Further, the heavy metals safety of consuming the plant for medicinal purposes remains unknown. In this study, metabolite profiling of the methanolic stem bark extract of E. delevoyi was performed using a de-replication approach by coupling HPLC-ESI-QTOF-MS with MZmine 3 based two molecular networking approaches, that is, GNPS (global natural products social molecular networking) and METLIN Gen2. Varieties of metabolites were tentatively identified for the first time in E. delevoyi. Health risk assessment was achieved by analysing the presence and concentration of heavy metals such as Ag, Al, As, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Se, Si, Sn, U and Zn using inductively coupled plasma optical emission spectroscopy (ICP-OES). Further, estimated daily intake (EDI), hazard quotients (HQ), and carcinogenic risk were determined. The utilization of qualitative tests to screen metabolite classes and the molecular networking tools revealed a detailed phytochemical profile of this medicinal plant species. Qualitative metabolite screening tests revealed the presence of flavonoids, alkaloids, phenolics, saponins, anthraquinones, terpenoids, steroids, cardiac glycosides, anthocyanins, and tannins in the methanol extract. LCMS2 coupled to mzmine3.6 revealed the presence of thirty-five metabolites from MoNA database. In addition, LCMS2-GNPS revealed the presence of twenty-six metabolites, and LCMS-METLIN Gen2 revealed a further sixteen compounds. Furthermore, total polyphenolic content and antioxidant (1,1-diphenyl-2-picryl-hydrazylhydrate - DPPH) capacities were assayed. Total phenolic content was 169.46 ± 0.71 mg GAE/g and total flavonoid content was 53.14 ± 1.78 mg QE/g. The crude extract had significant total polyphenolic content and antioxidant potential (IC 50 = 48.91 µg/mL) compared to the standard, ascorbic acid (IC 50 = 74.47 µg/mL). This plant, full of bioactive compounds and significant antioxidant properties, offers unique health solutions and robust possibilities for future drug development and pharmacology research. Although the bark of E. delevoyi possesses many health-promoting bioactive metabolites, the heavy metals evaluated in the bark of E. delevoyi in this study have carcinogenic risk (Al, 0.096; Cd, 0.002; Cr, 1.271; Ni, 0.024). Based on the non-carcinogenic health risk evaluation, E. delevoyi bark may be safe. However, its safety can only be determined if the plant's health risks are fully described in extensive chronic toxicity tests. E. delevoyi should therefore be used with caution in medicinal preparations. [ABSTRACT FROM AUTHOR]