There are no standard protocols for peristomal skin care in children with percutaneous endoscopic gastrostomy (PEG) tubes. This clinical study aimed to evaluate the efficacy of topical sucralfate as a prophylactic intervention in the peristomal wound reaction (PWR)/infection-associated PEG insertion in children. This study was a randomized, single-blind, controlled trial recruiting child under 18 years old who submitted for PEG insertion. Patients were randomly divided to receive topical sucralfate + peristomal wound care (intervention) or peristomal wound care alone (control). In the intervention group, the participants used topical 4% sucralfate cream four times a day for 2 months. Participants were assessed using the total peristomal infection score and PWR grading system at baseline week 1, and monthly up to 5 months after the initiation of the study. Forty-four children after PEG insertion were randomly assigned to two groups. Baseline characteristics of both groups were statistically similar (p > 0.05). Friedman test demonstrated statistically significant differences in grades of PWR during the follow-up period in the control group (p = 0.01); while there was not significantly different in the intervention group (p = 0.47). This finding suggests that the intervention had a prophylaxis effect. Also, there were statistically differences in the score of erythema (p = 0.001) and exudate (p = 0.06) at the seventime points in the control group. Topical 4% sucralfate can be considered an affordable and available prophylactic treatment for reducing the PWR/infection associated with PEG insertion in children.