This systematic review analyzed the prevalence of neglected tropical diseases (NTDs) and associated risk factors in the Amhara region. Thirty-one articles from 2012 to 2022 were examined, and data analysis was conducted using STATA version 17. The overall NTD prevalence in Amhara was 29.9% (95% CI: 23.32–36.47). The highest prevalences were observed for soil-transmitted helminths (STHs) at 37.86% (95% CI=27.57–48.15), Schistosoma at 37.77% (95% CI=16.90–58.61), scabies at 24.28% (95% CI=6.42-42.15), and trachoma at 19.55% (95% CI=13.38–25.72). Prevalence varied across zones, ranging from 6.10% (95% CI=4.33–7.87) in Awi to 46.40% (95% CI=42.90–48.80) in Bahir Dar. Factors associated with NTDs included illiteracy and raw vegetable consumption for STHs; male gender, river swimming, and contact with river water for Schistosoma; ocular discharge and fly-eye contact for trachoma; and family size >6, clothes sharing, and sleeping with scabies-infected individuals for scabies. Improved sanitation, health education, and personal hygiene are vital for controlling NTDs in the study region.