Background: Neonatal sepsis is a major cause of morbidity and mortality among low birth weight (LBW) infants. Central venous catheters, such as Umbilical Venous Catheters (UVCs) and Peripherally Inserted Central Catheters (PICCs), are commonly used in Neonatal Intensive Care Units (NICUs) for prolonged vascular access. While UVCs provide rapid access, PICCs are preferred for long-term use due to a potentially lower risk of complications. Objectives: The primary objective was to evaluate the impact of UVCs and PICCs on neonatal sepsis rates. Secondary objectives included assessing their effects on other neonatal health outcomes such as retinopathy of prematurity, necrotizing enterocolitis, local site infection, catheter blockage, bronchopulmonary dysplasia, and mortality. Methodology: A single-center randomized controlled trial was conducted on 162 neonates admitted to the NICU of tertiary care teaching institute, over 24 months. Infants were randomly assigned to the UVC (n=81) or PICC (n=81) groups. Data on sepsis incidence, catheter-related complications, and clinical outcomes were analysed using statistical tests, with a significance level of p<0.05. Results: Sepsis rates were comparable between UVC (54.3%) and PICC (51.9%) groups (p=0.43). Complications, including catheter blockage, displacement, necrotizing enterocolitis, and positive blood cultures, showed no significant differences. Mortality was slightly higher in the UVC group (18.5%) than in the PICC group (13.6%) but was not statistically significant. Conclusions: Both UVCs and PICCs are viable options for central venous access in LBW neonates, with no significant difference in neonatal sepsis incidence or overall complications. The choice of catheter should be based on clinical necessity and patient condition.