<i>Ganoderma lucidum</i> is a medicinal mushroom that has been used since ancient times. We studied whether chronic oral administration of <i>G. lucidum</i> extract withstands increases in levels of proinflammatory TNF-α and lipid peroxide (LPO), an indicator of oxidative stress, in the gingival tissues of periodontitis model rats. <i>G. lucidum </i>extract was initially examined for inhibition of <i>in vitro</i> oxidative stress, produced by Fenton's reagents in whole homogenates of fresh gum tissues from rats. Prior to <i>in vivo</i> and <i>in vitro</i> experiments with rats, <i>G. lucidum</i> extract was quantitatively tested for its total polyphenol and/or flavonoid contents and ability to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH)-free radicals. Chronic oral administration of <i>G. lucidum </i>extract (300 mg/kg BW) significantly decreased TNF-α and LPO levels in the gingival tissues of periodontitis model rats. <i>G. lucidum</i> extract also inhibited (<i>P</i> < 0.05) <i>in vitro</i> oxidative stress, as indicated by reduced levels of LPO in <i>G. lucidum </i>extract-preincubated gum tissue homogenates of fresh rats. The <i>in vitro</i> results were, thus, consistent with the <i>in vivo</i> inhibition of lipid peroxidation, DPPH free radical-scavenging effects, and the presence of total polyphenols/flavonoids in <i>G. lucidum</i> extract. Our results provide the evidence, at least partially, for the beneficial effects of <i>G. lucidum</i> on periodontitis, an inflammatory condition of gums which is associated with oxidative stress and preceded by infectious gum diseases.