Apocynum hendersonii is a traditional medicinal plant used primarily as tea. It has a potential health benefit from its rich bioactive substances. This study investigated the reactivity of solvents of different polarities (ethanol, ethyl acetate, n-hexane, methanol, and water) extracts of the A. hendersonii leaf. The phytochemical composition of the extracts was evaluated using a Fourier Transform Infrared spectrophotometer (FT-IR), Gas Chromatography-Mass Spectrometry (GC-MS), UHPLC-MS, and Higher Performance Liquid Chromatography (HPLC). The result revealed the presence of medicinally important bioactive constituents, including phenols, flavonoids, and polysaccharides. Methanol extracts exhibited the highest flavonoid contents (20.11 ± 0.85 mg QE/g DW) and the second-highest in terms of phenolic (9.25 ± 0.03 mg GAE/g DW) and polysaccharide (119.66 ± 2.65 mg GE/g DW). It also had the highest antioxidant capacity with 60.30 ± 0.52% and 4.60 ± 0.02 µmol Fe2+ per g DW based on a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and ferric reducing antioxidant power (FRAP), respectively. Ethanol extract displayed the maximum antibacterial action against Gram-negative and Gram-positive bacteria and the highest inhibition activity against the enzymes tyrosinase and acetylcholinesterase, followed by methanol extract. The principal component analysis revealed a positive correlation between the constituents, bioactivities, and extracts. The overall result showed A. hendersonii as a rich natural source of antimicrobial and antioxidant bioactive compounds and may be used for future applications in pharmaceuticals and food industries.