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Poor wastewater management in sub-Saharan Africa contributes significantly to infectious disease transmission and antimicrobial resistance (AMR) development, representing a critical One Health challenge at the human–environment interface. While technical solutions exist, sustainable behavior change requires understanding local knowledge systems and community dynamics. Effective AMR prevention cannot be achieved without robust community-centered health education that addresses environmental pathways of resistance development. This study examined how culturally tailored social science approaches can improve household wastewater management practices in Nigerian communities to combat AMR through a One Health lens. We conducted a comprehensive Knowledge, Attitudes, and Practices (KAP) study across seven districts in Gombe Metropolis, Nigeria (n = 320), followed by a quasi-experimental (non-controlled) 12-week community-centered health education incorporating One Health principles in the lowest-performing district. No biological samples were collected, all outcomes were based on self-reported knowledge, attitudes, and practices assessments. The intervention addressed AMR awareness gaps, environmental transmission pathways, and integrated human-environmental health considerations using local knowledge systems, community leadership structures, and culturally appropriate communication strategies. Baseline assessment revealed critical knowledge-practice gaps despite moderate correlations among domains (r = 0.51–0.57), with knowledge explaining only 26–32% of variance in attitudes and practices: while 39.7% demonstrated high knowledge levels, only 20% had heard of AMR, and 81% disposed of expired medications improperly, practices directly contributing to environmental AMR development. Gender differences favored males across all domains (p < 0.05), and income strongly influenced performance (p < 0.001). Post-intervention assessment revealed substantial changes in addressing these One Health challenges: knowledge scores increased by 80% (2.5 to 4.5, p < 0.001), AMR awareness rose substantially, and self-reported practice adoption showed 60% improvement (2.5 to 4.0, p < 0.001), including better medication disposal practices. Attitude changes remained moderate, reflecting persistent structural constraints including inadequate waste management infrastructure, limited municipal sanitation systems beyond household control, and socioeconomic barriers requiring longer-term One Health interventions. While the quasi-experimental design limits definitive causal attribution, these findings suggest potential benefits of culturally adapted health education approaches. Community-centered health education interventions respecting local knowledge while introducing evidence-based One Health practices offer promising pathways for bridging knowledge-practice gaps in AMR prevention. The persistence of moderate attitudes despite improved knowledge and practices highlights that effective AMR control requires sustained, multi-faceted community engagement addressing both individual behaviors and systemic infrastructural barriers, as attitude formation depends not only on education but also on enabling environmental conditions that facilitate safer practices. These findings have important policy implications for urban environmental health planning in Nigeria, suggesting that effective AMR prevention strategies should integrate community health education with improvements in municipal waste management infrastructure, establishment of medication take-back programs, and cross-sectoral coordination among health, environmental, and urban planning agencies.