Background: Mortality is one of the demographic variables that affect population trends. Among mortality of children, Infant mortality contributed to more than 75% of all under-five deaths globally. It disproportionately affects those living in the different regions of countries and within the region. Exploring the spatial distribution and identifying associated factors is important to design effective intervention programs to reduce infant mortality. Thus, the aim of this study was to assess the spatial distribution and associated factors of infant mortality in Ethiopia using 2016 Ethiopian Demographic and Health Survey (EDHS). Method: This study used the 2016 EDHS data as a data source. The 2016 EDHS data collected using a two-stage sampling method. A total weighted sample of 11,023 live births was used. Spatial analysis was done to explore spatial distribution of infant mortality using ArcGIS version 10.4. The study was evaluated different statistical models: the first model was analyzed the data using empty multilevel model without predictors, the second model was adjusted for individuallevel factors, the third model was adjusted for both individual and community-level factors, the fourth model was adjusted for spatial effects in addition to individual and community level factors. Model comparison was done by using -2 Log-likelihood, AIC, and BIC. Of those models, the model that accounts for the spatial effect was the relatively best model that manifests the data in the study, and hence this model was used to identify factors associated with infant mortality. Results: This study revealed that the spatial distribution of infant mortality was non-random in the country with Moran’s index 0.1546 (P-value=0.0185). The Afar and Somali regions of Ethiopia were identified in this study on the hot spot of infant mortality. Male infants (OR=1.59; 95%CI:1.29,1.95), smaller birth size (OR=1.27; 95%CI:0.79,1.60), multiple birth type (OR=6.82; 95%CI:4.75,10.80), ANC, birth interval, birth order, breastfeeding status, poor wealth index, rural residence, region, and the spatial variable (Si) were significantly associated with infant mortality in Ethiopia. Conclusions: Spatial distribution of infant mortality varies across the country. ANC usage, sex of a child, birth interval, birth size, birth type, birth order, wealth index, residence, region, and the spatial variable (Si) were significant predictors of infant mortality. Therefore, it needs great interventions in the hot spot areas. Focusing on maternal health care services, rural residences, multiple births, infants having a smaller birth size and male infants deserves special attention.