The South African National Department of Health published updated guidelines in 2019 for the prevention of mother-to-child transmission of communicable diseases. The proposed management of a neonate born to a mother with tuberculosis (TB) was included, and recommended referral of all symptomatic TB-exposed neonates to hospital for TB evaluation. However, no standard approach exists for evaluating hospitalised, symptomatic TB-exposed neonates, including preterm and low-birthweight (LBW) neonates born to mothers with TB. We use a clinical case report to illustrate a suggested approach to hospital-based evaluation of TB-exposed neonates, including preterm and LBW neonates. Guidance for the interpretation of different TB screening investigations in this population is also provided.