Background: Childhood diarrheal illness is the second leading cause of child mortality in Sub Saharan Africa, including Ethiopia. Studies hypothesized that there are regional variations. Thus, the study aimed to examine the spatial variations and to identify the determinants of childhood diarrhea in Ethiopia. Methods: Data from the 2016 Ethiopia Demographic and Health Survey (EDHS) was analyzed. This nationwide survey involved 10,337 children below 5 years old. The survey was carried out using a two-stage stratified sampling design. Moran’s I and LISA were used to detect the spatial clustering of diarrhea cases and to test for clustering in the data. Descriptive statistics followed by a mixed-effect logistic regression was used to identify the factors associated with the prevalence of diarrhea. Results: Overall, 11.87% of children were experienced childhood diarrheal illness. The study reveals high-risk areas were Southern and central Ethiopia, while eastern and west were indicated as low-risk regions. Younger children were more likely to suffer from childhood diarrhea than their older counterparts: age 6 to 12, 12 to 23, and 24 to 35 months were (AOR = 2.66, (95% CI 2.01, 3.52)), (AOR = 2.45, (95% CI 1.89, 3.17)), and (AOR = 1.53, (95% CI 1.17, 2.01)), respectively. Children living in Tigray (AOR= 1.69 (95% CI, 1.01, 2.83)), Amhara (AOR = 1.80, (95% CI, 1.06, 3.06), SNNPR (AOR = 2.04, 95% CI 1.22, 3.42), and Gambela (AOR = 2.05, (95% CI 1.22, 3.42)), faced greater risk than Addis Ababa city. The odds of getting diarrhea is decreased by 24% among households having ≥3 under-five children as compared to households having only one under-five child (AOR = 0.76 (95% CI: 0.61, 0.94)). The odds of children getting diarrheal illness among working mothers increase by 19% as compared to not working (AOR = 1.19 (95% CI 1.03, 1.38)). Conclusions: childhood diarrheal illness is highly prevalent among under-five children, particularly in SNNP, Gambella, Oromia, and Benishangul Gumuz regions. Capacity building programs with best experience sharing and better household environment may prove effective in reducing the incidence of childhood diarrhea in Ethiopia. Keywords: Spatial statistics, Ethiopia, under-five children, Diarrhea, Generalized Mixed Model