This PROSPERO-registered systematic review synthesized global evidence on gut microbiome differences between complicated and uncomplicated pediatric appendicitis. Twenty-one studies across 14 countries were included after PRISMA screening. The most significant biomarker identified was Fusobacterium species, which was associated with a 53.1% complication rate versus 32.3% in patients without Fusobacterium (RR = 1.64). Notably, this association was stronger in high-income countries, indicating geographic and socioeconomic influences on microbiome composition. Complicated appendicitis was also characterized by higher microbial diversity, increased anaerobic species, and greater prevalence of pathogens such as Pseudomonas aeruginosa, Enterococcus spp., and Bacteroides fragilis. These findings support the potential for microbiome-based risk stratification, personalized antibiotic selection, and improved clinical decision-making. Future directions include multicenter validation studies, prediction-tool development, and exploration of microbiome-targeted interventions.