Background <p>The incidence of neonatal sepsis in the United States of America is 1–2 cases per 1,000 live births. The majority are bacterial infections due to <i>Escherichia coli</i> and Group B Streptococcus. Only a few reported cases due to <i>Streptococcus mitis oralis</i> exist in the literature with limited information regarding management and treatment.</p> Case presentation <p>We report a case of <i>Streptococcus mitis oralis</i> bacteremia and meningitis in a full-term 38 week and 6-day-old female neonate born to a 37-year-old G2P2 mother initially treated with ampicillin and gentamicin for presumed Group B Streptococcus (GBS) sepsis and meningitis, then completing a 14-day treatment course with cefepime.</p> Conclusion <p>Clinicians should be aware of <i>S. mitis oralis</i> as it can cause significant illness in both pre-term and term neonates, a population more susceptible to infection. Due to the low incidence of cases, there are no specific guidelines for management of <i>Streptococcus mitis</i> sepsis or meningitis in the newborn. We highlight our clinical decision-making regarding antibiotic selection and treatment duration while focusing on enhancing treatment efficacy based on antimicrobial susceptibilities.</p>