Lithium is a first-line treatment for bipolar disorder, a disorder that is characterized by alternating manic and depressive episodes. However, because of its narrow therapeutic index, lithium can cause adverse effects. The association of lithium with more complex molecules, such as proteins and polysaccharides, may help control the release of lithium throughout the digestive system, thereby reducing the doses that are used by patients and consequently reducing adverse effects. The present study evaluated the acute oral toxicity of lithium bioaccumulated in mycelial biomass of Ganoderma lucidum, a research step that precedes preclinical efficacy studies. The study followed Organization for Economic Cooperation and Development guideline. Male Wistar rats (n = 6) were acutely treated by gavage with fixed doses (300 and 2000 mg/kg) of lithium bioaccumulated in mycelial biomass of G. lucidum. Changes in clinical signs, body mass, relative organ mass, biochemical parameters, blood count, leukocytes, and histopathological changes were evaluated. A group of animals that were treated with vehicle (n = 6) served as the basal group. No signs of toxicity were observed in any of the investigated parameters. Lithium bioaccumulation in mycelial biomass of G. lucidum did not induce signs of toxicity in rats that were acutely orally treated.