Phytochemical investigation of Polyscias guilfoylei leaves extract (PGE) led to the isolation of nine compounds, that is, ent -labda-8(17),13-diene-15,18-diol ( 1 ), stigmasterol ( 2 ), spinasterol ( 3 ), N -(1,3-dihydroxyoctadecan-2-yl) palmitamide ( 4 ), panaxydiol ( 5 ), 3- O - β - d -glucopyranosylstigmasta-5,22-diene-3- β -ol ( 6 ), (8 Z )-2-(2 hydroxypentacosanoylamino) octadeca-8-ene-1,3,4-triol ( 7 ), 4-hydroxybenzoic acid ( 8 ), and tamarixetin 3,7-di- O - α -L-rhamnopyranoside ( 9 ). Compound 4 is reported in this study for the first time in nature whereas compound 9 is reported for the second time. Structural elucidation of the compounds was carried out using Nuclear Magnetic Resonance and Electrospray Ionization coupled with Mass Spectrometry spectroscopic analyses. PGE and compounds 4 and 9 exhibited weak cytotoxicity against both MCF-7 and HCT-116 cell lines using 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide assay. The antimicrobial activity of PGE and compounds 4 and 9 was evaluated using the agar diffusion method. Escherichia coli was the most susceptible Gram-negative bacteria toward PGE with a minimum inhibitory concentration value of 9.76 μg/mL, whereas compounds 4 and 9 did not show any antimicrobial activity. Compound 4 exhibited promising inhibition of histamine release using U937 human monocytes with an IC 50 value of 38.65 μg/mL.