Peripherally inserted central catheter (PICC) is an important treatment for the drug and nutrition administration in neonates. We aimed to evaluate the effects and safety of PICC placement through upper versus lower limb vein in neonates, to provide insights into the clinical PICC nursing care. A meta-analysis. We searched the Cochrane Library, Web of Science, PubMed, Science Direct, China national knowledge infrastructure, Wanfang Data Knowledge Service Platform, China Weipu Database, China Biomedical Literature Database for published randomized controlled trials (RCTs) on the placement of PICC via upper limb and lower limb venipuncture. Two reviewers independently evaluated and cross-checked the quality of the included studies in accordance with the quality standards of the Cochrane Manual. We used RevMan 5.3 software for statistical processing. A total of 12 RCTs were included in this meta-analysis. Meta-analysis indicated that compared with upper limb veins, PICC insertion through lower limb veins is beneficial to increase the one-time puncture success rate (relative risk [RR] = 0.73, 95% confidence interval [CI]: 0.68-0.79) and the indwelling time (mean difference [MD] = -3.60, 95% CI: -5.35 to -1.86), reduce the operation time (MD = 10.37, 95% CI: 7.48-13.26), estimated bleeding volume (MD = 0.55, 95% CI: 0.34-0.75), incidence of catheter ectopia (RR = 2.46, 95% CI: 1.81-3.35), PICC-associated infection (RR = 2.82, 95% CI: 1.65-4.83), exosmosis (RR = 2.45, 95% CI: 1.49-4.04, p < .001) and phlebitis (RR = 1.40, 95% CI: 1.03-1.90). No significant difference in the Incidence of catheter obstruction between the upper and lower limb veins (RR = 1.20, 95% CI: 0.73-1.97, p = .48) was found. There are certain advantages in neonatal PICC puncture through the lower limb vein. The lower limb vein may be the preferred choice for neonatal PICC puncture.