OBJECTIVE: Anxiety and depression are common psychiatric disorders that affect millions of people worldwide. Lipopolysaccharide (LPS) is a bacterial endotoxin that has been demonstrated to cause depression and anxiety-like behaviors in animal models. Fustin is a flavonoid found in various plant species that have been reported to have neuroprotective effects. The study proposed the evaluation of fustin's impact on anxiety and depression in LPS-injected rats. MATERIALS AND METHODS: The efficacy of fustin in higher and lower doses was studied by administering a single dose of LPS-injected anxiety/depression in rodents. Behavioral models like the elevated plus maze test, open field test, marble burying test, force swimming test, tail suspension test, and hyperemotionality behavior were performed to evaluate anxiety/depression in rodents. The neuroinflammatory markers such as interleukin-6 (IL-6), interleukin-1β (IL-1β), nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), apoptosis marker caspase-3, and brain-derived neurotrophic factor (BDNF) were also measured as a part of the study. Additionally, biochemical markers of oxidative stress, such as malonaldehyde (MDA) and antioxidants, including superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and nitric oxide (NO), were also evaluated. RESULTS: LPS administration resulted in significant (p<0.001) changes in behavior tests and biochemical markers including IL-1β, IL-6, NF-κB, TNF-α, NO, caspase-3, BDNF, MDA, CAT, SOD, and GSH. In contrast, treating the rats with fustin significantly improved the behavior tests and restored the changes in biochemical markers. CONCLUSIONS: The current work established the efficacy of fustin with its therapeutic impact on depression and anxiety-like behaviors in rodent experimental models through its modulation of apoptosis markers, oxidative stress, and neuroinflammation.