Strongyloides stercoralis infection is one of the most neglected parasitic infections in the globe. However, its true prevalence is under-reported in the tropics and subtropics due to diagnostic challenges and limited knowledge on its public health importance. Ivermectin (IVM) is the first line drug to treat S. stercoralis infection, although there are conflicting reports on the efficacy of single-dose IVM. Factors associated with S. stercoralis infection are also poorly addressed in endemic countries. This study aimed to assess spatial distribution, efficacy of single-dose IVM (200µg/kg), performance of diagnostic methods and associated factors of S. stercoralis infection among schoolchildren in Amhara National Regional State. A cross-sectional study was conducted among randomly selected 844 schoolchildren from April to December 2019. A structured questionnaire was used to collect data on associated risk factors. A stool sample was collected from each participant and analyzed for S. stercoralis with formol ether concentration technique (FECT), spontaneous tube sedimentation technique (STST), Baermann concentration technique (BCT), agar plate culture (APC), and real-time polymerase chain reaction (RT-PCR) techniques. The data were entered using EpiData Software and analyzed by Stata SE 14 and Statistical Package for Social Sciences (SPSS) version 22 softwares. Prevalence and cure rate (CR) of IVM were calculated using descriptive statistics. The composite reference and Kappa value were used to calculate the performance and degree of agreement, respectively. The sensitivity and specificity of diagnostic methods were evaluated against the composite reference. The agreement of diagnostic methods was evaluated by Kappa value. The strength of association between S. stercoralis infection and associated factors was computed by logistic regression. The variables were statistically significant if p-value was less than 0.05. According to these finding, prevalence of S. stercoralis using a combination of five methods was 39.0% xix (329/844) among 844 schoolchildren. The prevalence of S. stercoralis infection among schoolchildren in the highlands, semi-highlands and lowlands areas of Amhara Region were 40.4%, 41.8% and 25.9%, respectively. The detection rates of S. stercoralis by RT-PCR, APC, BCT, STST and FECTs were 28.8%, 10.9%, 10.3%, 4.0% and 2.0%, respectively. The sensitivity of RT-PCR, APC, BCT, STST and FECT against the composite reference was 73.9%, 28.0%, 26.4%, 10.3% and 5.2%, respectively. The agreements of RT-PCR with the composite reference was substantial (0.775). The CR of single-dose IVM against S. stercoralis infection was 94.6%. Schoolchildren in age groups of 10-11 and 12-14 years, being male, living in rural area, having abdominal pain, cough, and skin rash, wearing shoes irregularly, participating in irrigation, playing with soil, living around wet environment, sandy and semi- highland were significantly associated (p<0.05) with S. stercoralis infection. In conclusion, prevalence of S. stercoralis is high among schoolchildren and in semi-highland areas of Amhara region. A combination of diagnostic methods has better sensitivity. A single-dose IVM is effective to treat S. stercoralis infection. Socio-demographic, clinical, personal, and environmental factors are significantly associated with S. stercoralis infection. Therefore, use of combined diagnostic methods and single-dose IVM for case management of patients should be advocated for effective prevention and control measures.