A prospective cohort study of 1,400 Zambian children under five documented 230 first episodes of Shigella infection over 9.5 months, yielding an incidence of 24.0 cases per 1,000 child-months. Whole-genome sequencing revealed extensive multidrug resistance across trimethoprim, aminoglycosides, and beta-lactams, with concerning plasmid-mediated quinolone resistance emerging in S. flexneri strains. Crucially, all isolates remained sensitive to macrolides, Zambia's first-line treatment. This finding carries significant implications for global antibiotic stewardship and childhood mortality reduction in low-resource settings. Shigella remains a top-three cause of diarrheal death in children worldwide, making resistance patterns critical for treatment protocols. The preserved macrolide sensitivity offers a therapeutic lifeline, though the identified plasmid-mediated resistance mechanisms suggest this advantage may be temporary. The study's strength lies in its community-based design and genomic characterization, though generalizability beyond peri-urban Zambian populations requires confirmation. As a preprint awaiting peer review, these resistance patterns and incidence rates require validation before informing clinical guidelines, but the data suggests an urgent need for enhanced surveillance and antibiotic stewardship programs.