In this report, we have attempted to analyze the neonatal toxicities of SMX-TMP in an unbiased manner. Our review of the literature indicates there is a clear lack of evidence showing the occurrence of kernicterus in neonates when SMX-TMP is used orally to treat pneumonia or sepsis. However, studies that demonstrate the occurrence of kernicterus resulting from sulfisoxazole warrants the necessity of follow-up studies to ensure the complete safety of SMX-TMP in neonatal population. To achieve this, there is a need for further focused clinical studies in humans as well as animal-based studies conducted in newborns to address the effect of SMX-TMP to test its ability to cause kernicterus and address the safety issues in neonates. Collectively, our review provides an analysis of the possibility of neonatal kernicterus after oral use of the SMX-TMP combination. Although it has been shown that SMX-TMP does not directly cause neonatal kernicterus, it does not rule out any other toxicity that could be caused by SMX-TMP. We therefore recommend that clinical studies that focus on evaluating the effects of short- and long-term use of SMX- TMP in home-based neonatal care need to be conducted. The review also warrants the need for future studies to analyze the safety profile of SMX-TMP.