Four unprecedented nortriterpenoids, masterpenoids A-D, were isolated and fully elucidated from the resin of the mastic tree (Pistacia lentiscus). Masterpenoids A-C are the first norterpenoids featuring an unprecedented 6/6/6/10 ring system, while masterpenoid D possesses a novel 6/6/6/7/5 ring system. The anti-inflammatory potential of the compounds was meticulously assessed through the establishment of an in vitro model of lipopolysaccharide-induced inflammation in RAW264.7 macrophage cells. Among them, Masterpenoids A and D showed potent inhibition of NO production, with IC50 values of 10.6 ± 0.8 and 8.2 ± 0.9 μM, respectively, compared to positive control dexamethasone (IC50 = 23.2 ± 1.2 μM).