The main aim of this study was to identify determinants of prevalence of diarrhea, to describe spatial dependence of diarrhea and develop models specifying risk factors used to diagnosis of diarrhea among districts in SNNPR and Oromia Regional States of Ethiopia by using 2011 EDHS collected for 144 weredas/districts by employing spatial models. Spatial lag and spatial error model were fitted to the data, though spatial lag model specification was taken as the best fit for diarrhea prevalence rate. Accordingly, from global and local spatial analysis it was found that diarrhea prevalence rate in one district was directly affected by that of its neighbors. The results revealed that water closet, proportion of children under five, toilet availability, and mother’s basic education attainment, vaccination coverage, size at birth, mother current working status, ORS information, altitude, stunting score and wasting score of children were significant determinants of diarrheal infection rate. Thus, it is suggested that the geographically targeted preparation on accumulation of treatment that can be useful to control and stabilize spillover (nearest area spread) of disease over space. It can be suggested for this states that the government needs to make intervention to mitigate the spatial variation of the diarrhea prevalence across regions.