Introduction: Schistosomiasis is one of the Neglected Tropical Diseases in Ethiopia. Since 2015, yearly school-based mass drug administration (MDA) using praziquantel has become the major control strategy. This study aimed to assess trends of Schistosoma mansoni infection in a high-endemic area in Northwest Ethiopia. Methodology: Data were extracted from routine laboratory logbooks at two health centers in West Dembia district, Amhara region, for the period 2013-2018. Wet-mount direct microscopy was used to diagnose intestinal parasites. Chi-square test was used to compare proportions of S. mansoni-positive results before and after the start of MDA with praziquantel, across sex, age groups, and seasons. Results: Data of 8002 stool tests was extracted. The proportion of S. mansoni progressively decreased from 9.6% in 2013 to 4.1% in 2018 in the overall patient population and from 20.3% in 2013 to 8.8% in 2018 in school-aged children. However, a declining trend of S. mansoni was observed before the launch of MDA and remained constant after the start of the MDA. The positivity rate was significantly higher in males and in the 5-14 years age group. S .mansoni infection in school aged children showed significant seasonal variation. Conclusions: The declined trend of S. mansoni positivity rate is encouraging and may be related to the existence of intervention packages. Although the timing of MDA was related with low positivity rate of S. mansoni infection, it has not resulted in the expected beneficial effect. Therefore, the district health office should work on both MDA and other interventions.