Badam Talkh kuhi is an endemic species of Iran commonly used by native people as anti-inflammatory and antimicrobial remedy. The present study was aimed at investigating the folk claims of this plant, identified by us as Amygdalus lycioides Spach. Several extracts were prepared using various extraction procedures combined with solvents of different polarity. A decoction was firstly prepared according to the procedure of the folk medicine. Maceration (ME), Ultrasound- Assisted Extraction (USAE) and Microwave-Assisted Solvent Extraction (MASE) were then experimented using pure methanol (MeOH) and n-hexane-acetone (n-Hex-Ac, 50% v/v). Concerning biological investigation, the antimicrobial potential of all extracts was firstly evaluated by employing the growth inhibition test. Then, the free radical scavenging effect of each extract was measured, given that reactive oxygen species (ROS) are involved in TNFα-induced signaling pathways associated with inflammation. Finally, the anti-TNFα activity of the most active extracts was evaluated using in vitro and in vivo assays. Regarding the anti-inflammatory activity, decoction and MASE n-Hex/Ac extract inhibited the production of TNFα with IC50 in the range of 120-390 μg/ml and 6-20 μg/ml, respectively. Interestingly, after oral administration in mice, MASE n-Hex/Ac extract was effective in reducing TNFα of about 60%. Moreover, treated animals did not show any signs of toxicity. Results herein reported clearly evidenced that Amygdalus lycioides Spach could be a valuable source of TNFα-blockers effective against chronic inflammatory diseases..