As a naturally occurring flavonoid, 7,8-dihydroxyflavone (7,8-DHF) exhibits protective effects in preventing neurodegeneration by activating the tropomyosin receptor kinase B (TrkB). However, whether 7,8-DHF influences the progression of chronic diseases through TrkB-independent mechanisms remains largely unclear. Here, we discovered that 7,8-DHF could protect cells from oxidative stress-induced cell death by acting as a previously unrecognized inhibitor of ferroptosis. Ferroptosis is a form of programmed cell death caused by uncontrolled peroxidized phospholipids. Although 7,8-DHF functions as a neuron protector by acting as a TrkB agonist, our data demonstrate that 7,8-DHF suppresses ferroptosis independently of activating TrkB signaling pathways. Indeed, as natural radical-trapping antioxidants, 7,8-DHF directly neutralizes peroxidized phospholipids to inhibit ferroptosis in a GSH/GPX4-independent manner. Since the low bioavailability of 7,8-DHF in vivo limits its clinical uses, we developed engineered 7,8-DHF nanoparticles (7,8-NPs) to enhance its absorption and utilization in a pharmacokinetic model. Consistent with previous studies, we confirmed that 7,8-NPs effectively reduce Alzheimer's disease pathology. Moreover, we found that 7,8-NPs could alleviate ulcerative colitis by reducing inflammation and ferroptotic stresses, suggesting the critical role of 7,8-DHF against ferroptosis in vivo. These observed effects on ferroptosis inhibition demonstrated that 7,8-DHF exhibits a molecular signature associated with improved colon health.