Anxiety disorders can associate with oxidative stress and immune system alterations. Our study aimed to chemically analyze Hypericum maculatum (HM) and Hypericum perforatum (HP) dry extracts and to evaluate their effects along with quercetin (Q), on brain oxidative stress biomarkers: malondialdehyde (MDA), catalase (CAT) and superoxide dismutase (SOD), inflammatory cytokines: interleukin-1α, (IL-1α), IL-1β, regulated on activation normal T cell expressed and secreted (RANTES), interferon (IFN), monocyte chemoattractant protein-1 (MCP1), macrophage inflammatory protein (MIP) and serum corticosterone levels. Nuclear transcription factor κB (NFκB) signaling pathway in the hippocampus and frontal lobe in rats with N-methyl-9H-pyrido[5,4-b]indole-3-carboxamide (FG-7142) experimental-induced anxiety were also investigated. The chemical analyses of total hypericins were performed by spectrophotometric analysis and hypericin, hyperforin and polyphenols derivatives were quantified by chromatographic methods. The animals were divided in 6 groups: carboxymethylcellulose 2% (CMC); CMC + FG; alprazolam (APZ) + FG; Q + FG; HM + FG; HP + FG. APZ (0.08 mg/kg b.w.), Q (30 mg/kg b.w.), HM and HP (350 mg/kg b.w.) were orally administered for 21 days. FG (7.5 mg/kg b.w.) was intraperitoneally (i.p.) injected in a single dose. Q and hypericum extracts (HpE) exerted anti-inflammatory (decreased IL-1α, IL-1β, MCP1, IFN and MIP mainly in hippocampus) and antioxidant effects (decreased MDA levels, increased CAT and SOD activity), enhanced NFκB and pNFκB expressions in the brain and reduced serum corticosterone levels. Our findings suggest that HpE may improve anxiety-like behavior, offer brain protection by modulation of oxidative stress and inflammation, and can contribute to overall biological activity of natural compounds-rich diet.