The present study evaluates the phytochemical content and biological activities of eight Clerodendrum paniculatum leaf extracts obtained using four solvents of varying polarity and two extraction methods. GC-HRMS analysis of the hexane extract predicted presence of phytol, 22-tritetracontanone, and 6,9,12-octadecatrienoic acid, phenyl methyl ester, (ZZZ)-as major compounds, and ethyl acetate extract was predicted to contain phytol. LC-HRMS analysis of methanolic extract exhibited the presence of 8',10'-dihydroxydihydroergotamine, Khayanthone, Galactonic acid, Calotropin, and 26,26,26,27,27,27-hexafluoro-1alpha,24-dihydroxy vitamin D3 as significant fractions. Ethyl acetate extract showed significant antimicrobial activity in-vitro. Methanolic extracts possess the highest radical scavenging activity (up to 87%) and antidiabetic activity (up to 49%) at 1 mg/mL concentration. Methanolic extracts from maceration and the Soxhlet method showed better cytotoxicity against breast and oral cancer cell lines, while the aqueous extract from maceration demonstrated better cytotoxicity against lung cancer cell lines. Methanolic extracts containing tannins, flavonoids, alkaloids, quinones, glycosides, terpenoids, diterpenoids, and phytosterols demonstrated significant bioactivity.