The stem bark of Discopodium penninervium afforded a withanolide, 6α,7α-epoxy-1-oxo-5α,12α,17α-trihydroxywitha-2,24-dienolide (1) and a coloratane sesquiterpene, 7α,11α-dihydroxy-4(13),8-coloratadien-12,11-olide (4) along with five known compounds, withanone (2), 5α,17β-dihydroxy-6α,7α-epoxy-1-oxowitha-2,24-dienolide (3), 7α,11α-dihydroxy-8-drimen-12,11-olide (5), withasomnine (6), and (E,Z)-9-hydroxyoctadeca-10,12-dienoic acid (7). The identity of the compounds was established on the basis of spectroscopic data analysis. All compounds were assessed for inhibition of leukotriene metabolism in an in vitro bioassay using activated human neutrophile granulocytes, and for in vitro cycloxygenase-1 and -2 inhibition from sheep cotyledons and seminal vesicles, respectively. In the leukotriene biosynthesis assay all compounds tested at a concentration of 50 μM exhibited activity with percentage inhibitions ranging from 11.5 to 36.6. The withanolide, 1, displayed a 46.4% inhibition of COX-2 and a 22.9% inhibition of LTB4 formation at 50 μM concentration. Compounds 4 and 6 inhibited LTB4 biosynthesis but showed minor inhibition of COX-1 and COX-2. The remaining compounds, on the other hand, were found to be inactive on COX enzymes.