Two new tetrahydroisoquinoline alkaloids (1-2) were isolated from the edible and ethnomedicinal plant Portulaca oleracea using various chromatographic methods, alongside 53 known compounds (3-55). Their structures were ascribed using extensive NMR, MS and physiochemical analyses with 26 compounds (1-2, 5-6, 8, 10-11, 14-15, 17-18, 20-21, 23, 25-26, 44-53) isolated from P. oleracea for the first time. The potential antioxidant and anti-inflammatory applications for P. oleracea were supported by 14 of the isolated compounds (including 1 and 2) displaying DPPH radical-scavenging activities (EC50 = 6.68–64.04 μM), while a further 18 (including 2) exhibiting NO-inhibiting activities in LPS-stimulated RAW 264.7 macrophage cells (EC50 = 4.25–69.75 μM). © 2022