Considering that periodontitis is a chronic immunoinflammatory disease, the use of agents to modulate the host response has been investigated. Lycopene is a carotenoid hydrocarbon that exerts anti-inflammatory and antioxidant effects. This study aimed to evaluate whether the systemic lycopene administration reduces the harmful effects of induced periodontitis in rat molars. 108 male Holtzman rats were distributed into 3 groups: Control group (CG), Periodontitis group (PG), and Periodontitis group treated daily with 20 mg/kg of lycopene (PLG). Periodontitis was induced by ligature placement on the first upper molars. After 7, 35, and 70 days following periodontitis induction and lycopene treatment, the rats were anaesthetised and blood was collected to measure serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Maxillary and liver fragments were processed for morphological analysis, while gingival samples were collected to evaluate the gene expression of Il1b, Tnf , Tnfsf11, Tnfrsf11b, Mmp9, Nfkb1, and Mapk3 by RT-qPCR. Statistical differences were evaluated using a two-way ANOVA followed by Tukey’s post-test, with significance level set at p  <  0.05. Serum AST was significantly higher in PG samples than CG at all time points, and significantly lower in PLG than in PG at 35 and 70 days. In contrast, serum ALT concentrations showed no significant differences among groups or over time. No hepatic morphological changes were observed in the HE-stained sections in any of the groups. PLG specimens showed lower Tnf, Nfkb1, and Mapk3 mRNA levels at all time points and reduced Il1b expression at days 7 and 35, compared to the PG. Additionally, compared to the PG group, PLG specimens exhibited significantly reduced bone loss, junctional epithelium migration, inflammatory infiltrate in the gingiva, osteoclast counts, and RANKL/OPG ratio, alongside lower MMP-9 and cathepsin K immunoexpression in osteoclasts. These results demonstrated that lycopene mitigates periodontitis by reducing inflammation and attenuating alveolar bone loss via suppression of osteoclastogenesis and resorptive enzymes, representing a promising therapeutic agent.