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Combretum nioroense is widely used in the folkloric treatment of a variety of bacterial and helminthic infections. The decoction of its leaves is traditionally fed to newborn babies in some rural parts of Ghana. The study focused on identifying the prime components of petroleum ether and ethanolic extracts of the stem bark using standard phytochemical screening protocols and chromatographic and spectroscopic techniques. The activities (cytotoxicity, antimicrobial, antioxidant, anthelmintic, and anti-inflammatory) of the extracts of C. nioroense were also investigated. Preliminary phytochemical analysis of the extracts revealed the presence of glycosides, saponins, phenols, coumarins, alkaloids, flavonoids, tannins, steroids, phytosterols, flavanols, terpenoids, and cardiac glycosides. The action of the extracts of C. nioroense on Milsonia ghanensis worms was concentration-dependent, with the least concentration (0.75 mg/mL) paralyzing and killing M. ghanensis after the maximal exposure time. The IC50 values for petroleum ether and ethanol extracts in the DPPH assay were >100.0 and 27.940 ± 1.005 μg/mL and those of the H2O2 assay were 400.900 ± 3.400 and 322.500 ± 1.005 μg/mL, respectively. The total antioxidant capacities (TACs) for petroleum ether and ethanol extracts were 47.197 ± 0.533 and 57.968 ± 0.560 gAAE/100 g, respectively. The IC50 value for ethanol extract in the cytotoxicity studies was 115.4 ± 1.332 μg/mL. The MICs of the extracts against the test organisms were within the range of 0.0122–25.0 mg/mL. The extracts (petroleum ether and ethanol) showed a concentration-dependent increase in anti-inflammatory activity with IC50 values of 31.254 ± 0.359 and 24.402 ± 0.569 μg/mL, respectively. Chromatographic separations of the ethanol extract gave three fractions. FTIR analysis of the extracts and purified fractions revealed the presence of functional groups, confirming the presence of the phytochemicals identified in the screening test. The results indicate that both extracts of C. nioroense exhibit cytotoxicity, antimicrobial, antioxidant, anthelmintic, and anti-inflammatory activities, thereby proving the folkloric use to treat ailments caused by worms and microorganisms.