Species of genus Morchella are high-value edible mushrooms. They are sought after by culinary experts due to their aroma, flavor, meaty texture, and health benefits. M. rufobrunnea, M. sextelata, and M. americana were chosen in this study and investigated for their medicinal quality by using in vitro anti-inflammatory and antioxidant assays. This sampling represents conditions by which morels are produced (cultivated indoors, cultivated outdoors, and collected from natural habitats, respectively) for commercial markets. Both aqueous and methanolic extracts of all three morel species showed identical chromatographic and bioassay profiles, independent of their phylogenetic position or production method. In an antioxidant assay, aqueous and methanolic extracts of these mushrooms at 100 μg/mL inhibited lipid peroxidation (LPO) by 59%-62% and 33%-36%, respectively. In an anti-inflammatory assay using cyclooxygenase enzymes (COX-1 and COX-2), aqueous and methanolic extracts at 100 μg/mL showed COX-1 enzyme inhibition by 53%-57% and 30%-32% and COX-2 enzyme inhibition by 38%-44% and 16%-17%, respectively. Chromatographic purification and spectroscopic characterization of M. rufobrunnea extracts afforded five sugars (compounds 1-5), seven organic acids (compounds 6-13), three flavonoids (compounds 14-16), triglycerides, free fatty acids, and three sterols (compounds 17-19). This is the first report of COX-1 and COX-2 enzymes and LPO inhibitory activities of pure isolates (S)-morelid (compound 6), glutamic acid (compound 9), and brassicasterol (compound 19). This study also showed inhibitions of COX-1 (by 84%, 33%, and 37%), COX-2 (by 47%, 11%, and 22%), and LPO (by 74%, 48%, and 35%), respectively, at 25 μg/mL.