BACKGROUND The combined infection of actinomyces odontolyticus sepsis and cryptococcal encephalitis is rare in routine clinical practice. Thus, we presented this case report and literature review to provide clues to improve such patients' diagnoses and treatment processes. METHODS The main clinical manifestations of the patient were high fever and intracranial hypertension. Then, we completed the routine cerebrospinal fluid examination, biochemical detection, cytological examination, bacterial culture, and India ink staining. Firstly, the blood culture suggested actinomyces odontolyticus infection, considering the possibility of actinomyces odontolyticus sepsis and intracranial actinomyces odontolyticus infection. Accordingly, the patient was administered penicillin for treatment. Although the fever was slightly relieved, the symptoms of intracranial hypertension did not relieve. After 7 days, the characteristics of brain magnetic resonance imaging and the results of pathogenic metagenomics sequencing and cryptococcal capsular polysaccharide antigen suggested that cryptococcal infection. Based on the above results, the patient was diagnosed with a combined infection of cryptococcal meningoencephalitis and actinomyces odontolyticus sepsis. Anti-infection therapy with 'penicillin, amphotericin, and fluconazole' was provided, improving the clinical manifestations and objective indexes. CONCLUSIONS The combined infection of Actinomyces odontolyticus sepsis and cryptococcal encephalitis is first reported in this case report, and combined antibiotics with 'penicillin, amphotericin, and fluconazole' are effective.