The chemistry of essential obtained from the leaves of Senna podocarpa (Guill. Et Perr.) Lock from Nigeria is being reported. The hydrodistilled oil was analyzed by gas chromatography-flame ionization detector (GC-FID) and gas chromatography-mass spectrometry (GC-MS) techniques. The main constituents of the oil were 1,2-benzenedicarboxylic acid, mono (2-ethylhexyl) ester phthalate (26.6%) and β-elemene (27.9%). There were significant amounts of caryophyllene oxide (7.3%) and urs-12-en-24-oic acid, 3-oxo-methyl ester (5.5%). The antimicrobial activity of the essential oil was evaluated against a panel of seven bacteria and two fungal strain using agar diffusion and broth microdilution methods. Results had shown that the oil exhibited moderate to strong antimicrobial activity against the tested microorganisms. The activity zones of inhibition (ZI) ranged between 10.0 ± 0.2 mm and 28.3 ± 2.9 mm while the minimum inhibitory concentrations (MIC) ranged between 0.3 mg/mL 5.0 mg/mL, respectively. The chemical constituents and antimicrobial activity of the essential oil of Senna podocarpa were being reported for the first time.