Background: Though condemned and considered as a crime by the countries government, Female Genital Mutilation (FGM) remains a common public health problem in Africa and Ethiopia as well. Every year, more than 3 million females undergo FGM and most of them are in Africa. Thus, this study was aimed to assess the spatial distribution and associated factors of female genital mutilation in Ethiopia based on the Ethiopian demographic and Health Survey 2016 data. Method: This is a secondary data analysis of Ethiopian Demographic and Health Survey (EDHS) 2016 data based on 7,163 women who were included for the FGM interview. The data were weighted using sampling weight as recommended by the program. The MS Excel and ArcGIS 10.3 software were used for data cleaning and spatial analysis respectively. Global and local level clustering was assessed. For the none spatial data and the determinant factors, data cleaning and analysis were done using STATA 14. Since the data has significant clustering with the Intraclass Correlation Coefficient [ICC=0.61(0.56, 0.65)], a multi-level mixed-effect logistic regression model was fitted. Variables with a P-value <0.25 in the bi-variable analysis were fitted in the multi-variable analysis. Finally, variables with p-value <0.05 with 95% CI of adjusted odds ratio were reported as a statistically significant determinant of FGM. Result: Female genital mutilation was spatially clustered (Global Moran’s I: 0.48, p<0.001). Significant hot spot clusters were found in Eastern-Amhara, Oromia, Southern Nations Nationalities and Peoples (SNNP) regions, Dire-Dawa, and Harari. Mothers age >30 (AOR=2.41, 95% CI: 1.78,3.26) years, never in union (AOR=0.31, 95%CI: 0.22, 0.44), currently not working (AOR=0.71, 95%CI: 0.55, 0.92), women who considered FGM to be continued (AOR=2.86, 95%CI: 1.75, 4.68), not heard of FGM (AOR=0.22, 95%CI: 0.08,0.62), had no formal education (AOR=1.67, 95% CI: 1.03, 2.71), Muslim (AOR=3.90, 95%CI:2.5, 6.09) and protestant (AOR=1.76, 95%CI: 1.25, 2.97), and those who thought of FGM required by religion (AOR=1.99, 95%CI: 1.31,2.99) were found to be significant determinants of female genital mutilation.Conclusion: Female genital mutilation was spatially clustered with hotspot areas found:in Eastern-Amhara, Oromia, and SNNP regions, Dire-Dawa and Harari administrative. Age of the mother, religion, occupation, educational level, marital status, information about Female genital mutilation, and intention about FGM to be stopped or continued were significant determinants of female genital mutilation