Background: Despite many years of mass drug administration, Schistosoma mansoni remains endemic in Ethiopia.. Most prevalence studies rely on the less sensitive Kato-Katz (KK) technique, likely underestimating infection rates. Additionally, limited data on knowledge, attitudes and practices (KAP) hampers effective control efforts. Reports of reduced praziquantel (PZQ) efficacy exist, but comprehensive data is limited. Objective: To assess the epidemiology of S. mansoni infection in school-aged children (SACs) and adults, the performance of diagnostic methods, and the efficacy of PZQ across various transmission settings in northwest Ethiopia, from February to June 2023. Methods: A cross-sectional study was conducted in seven districts among 1,192 participants, 634 SACs and 558 adults. Data on KAP, and associated factors were collected using a structured questionnaire. S. mansoni infection was diagnosed using KK and real-time PCR (RT-PCR) on stool samples, and the point-of-care circulating cathodic antigen (POC-CCA) test on urine samples. Diagnostic performance was evaluated using latent class analysis (LCA) and compared to KK. A school-based single-arm prospective cohort study was conducted to determine the PZQ efficacy. Accordingly, 130 SACs tested positive by both KK and POC-CCA at baseline were treated with 40 mg/kg PZQ (Biltricide®) and re-evaluated after three weeks to determine cure rate (CR) and egg reduction rate (ERR). Descriptive statistics were used to summarize the prevalence, and logistic regression analysis was performed to identify factors associated with infection. Results: Of the 1,192 participants, 782 (65.6%) were infected with S. mansoni as determined by combined diagnostic tests - 452 (71.3%) SACs and 330 (59.1%) adults. Among 398 KK-positive samples, light, moderate and heavy infections accounted for 66.8%, 25.1%, and 8.0%, respectively. SACs exhibited higher mean egg counts than adults (147.95 vs. 96.61, p = 0.001). The KK method showed reduced sensitivity in low (54.6%) and moderate (67.0%) transmission areas, improving in high-endemic settings (88.6%) compared to LCA reference. In contrast, POC-CCA showed consistently high sensitivity (93.4 - 100%), though specificity declined in low (86.0%) and moderate (78.9%) transmission areas. Against KK, POC-CCA had high sensitivity (93.5%) and good negative predictive value (95.3%), but low specificity (62.5%). The RT-PCR showed strong sensitivity against KK (93.5%) and LCA (97.2%) with substantial agreement with LCA (κ = 0.75), but specificity dropped as endemicity increased VII (84.2% in low, 79.4% in moderate and 28.0% in high). Associated factors included urban residence, age 10-14, swimming habit, irrigation activity and lack of awareness in SACs, and male sex, age 18–30, barefoot water contact, swimming habit, irrigation activity and day labor in adults. Awareness of schistosomiasis was low (19.2%), and only a small proportion had good knowledge (7.9%), positive attitudes (13.1%) and safe practices (43.2%). Among 110 SACs who completed the PZQ efficacy study follow up, the KK-based CR was 88.2%, with a 93.5% ERR; cure was highest in light infections at baseline (p = 0.002). The CR based on POC-CCA test was 70.9% (t+) and 75.5% (t-). Adverse events occurred in 26 (23.6%) participants, all mild. Conclusions: A high prevalence of S. mansoni was observed in the study area. The KK method showed low sensitivity, particularly in low-transmission settings, while POC-CCA and RT-PCR performed well in all settings. A single dose of 40 mg/kg PZQ was effective and safe. The KAP levels were low both at school and community settings. Integrated control strategies - including health education, water, sanitation and hygiene, and sensitive diagnostics - are urgently needed. Adoption of the POC-CCA test is recommended to strengthen diagnosis and support schistosomiasis elimination in Ethiopia