Inflammation is an organism’s biological defense mechanism. Acute and chronic inflammation of the body triggers the production of pro- and anti-inflammatory pathways that can affect the content of cytokines in the brain and thus cause brain inflammation. Disorders such as depression and posttraumatic stress disorder (PTSD) are often associated with elevated inflammation. Recently, positive and promising clinical results of psilocybin for the treatment of depression and PTSD were reported. Thus, we decided to test whether psilocybin alone or in combination with eugenol, an anti-inflammatory and antioxidant agent, would prevent the increase in or decrease the content of cytokines in the brain of C57BL/6J mice injected with lipopolysaccharides (LPS). Two experiments were performed, one with pre-treatment of mice through gavage with psilocybin (0.88 mg/kg), eugenol (17.6 mg/kg), or combinations of psilocybin and eugenol (1:10, 1:20, or 1:50), followed by intraperitoneal injection of LPS, and the second, post-treatment, with initial injection with LPS, followed by treatment with psilocybin, eugenol, or their combination. Brain tissues were collected, and cytokines were analyzed by qRT-PCR, Western blot, and ELISA. Data were analyzed with a one-way ANOVA followed by Tukey’s post hoc test or with multiple unpaired t-tests. LPS upregulated mRNA expression of COX-2, TNF-α, IL-1β, and IL-6. All pre-treatments decreased the expression of COX-2 and TNF-α, with psilocybin alone and in 1:50 combination, with eugenol being the most effective. In the post-treatment, all combinations of psilocybin and eugenol were effective in reducing inflammation, with the 1:50 ratio displaying the most prominent results in reducing the mRNA content of tested cytokines. Western blot analysis confirmed the effect on COX-2 and IL-1β proteins. Finally, the ELISA showed that post-treatment with psilocybin + eugenol (1:50) demonstrated the best results, decreasing the expression of multiple markers including IL-6 and IL-8. This demonstrates the anti-inflammatory effects of a combination of psilocybin and eugenol in the brain of animals with systemically induced inflammation.