Background: Thymelaea microphylla Coss. et Dur. (Thymelaeaceae) (TM) is a rare medicinal plant endemic to Algeria. Leaves decoction is used in folk medicine for anticancer, anti-inflammatory, and antidiabetic properties. Objective: Herein, the antioxidant and anti-inflammatory properties of different extracts from leaves and flowers of Algerian TM were evaluated. Materials and Methods: The study was carried out by in vitro cell-free assays (antioxidant/radical properties), ex vivo experiments (inhibition of prostaglandin E2 and thromboxane B2 release in human whole blood) and in vitro experiments on cell systems (cytotoxicity on peripheral blood mononuclear cells, and protective effects on human vein endothelial cells exposed to TNF-α). Results: The acetone TM extract showed significant antioxidant properties and excellent anti-inflammatory and cyclooxygenase-inhibitory activity, together with lack of toxicity on normal human blood cells; furthermore, it was able to protect endothelial cells against dysfunction induced by TNF-α, as shown by decrease in cell death, e-selectin expression and leukocyte adhesion. Conclusion: On these bases, TM leaves and flowers appear to be a good source of bioactive compounds with significant antioxidant and antiinflammatory capability, and potentially effective in prevention and treatment of pathological conditions related to oxidative stress and inflammation, such as endothelial dysfunction.