IntroductionEffective intervention needed to reduce childhood diarrhea, a significant cause of morbidityin resource-limited settings. This intervention aimed to evaluate the effectiveness of handwashing with soap at critical times, home-based water treatment and both combinations to reduce childhood diarrheain hotspot areas of southwestern Ethiopia.MethodsCommunity randomized control with the factorial design was conducted in southwestern Ethiopia from July to October 30/2020. About 720 households were maintained and equally allocated for handwashing with soap at critical times, home-based water treatment, and both combined interventions having 180 households that were followed up for four months. Baseline data were collected at the first two weeks from 720 households of intervention groups. Data was processed and entered into EPI data version 3.02. Homogeneity of the baseline characteristics of the participant in both groups was checked at a p-value less or equal to 0.05. The incidence of childhood diarrhea per 100 per two weeks was measured in both groups. Mann-Kendall trend test was performed to check the statistical significance patterns of childhood diarrhea. Intention-to-treat analysis was used to compare the incidence of childhood diarrhea for both groups. A generalized estimating equation with a logit-link Poisson distribution family and the exchangeable working correlation,with robust standard error estimation, was used for the analysis of repeated observations of the incidence of childhood diarrhea in individuals over time. An unadjusted and adjusted incidence rate along with the corresponding 95% CI was analyzed by using a multivariable analysis to control potential confounders on Stata 14 software.ResultsChildhood diarrhea significantly decreased in all intervention groupsbut increasing in control groups. Particularly, handwashing with soap at critical times has reduced childhood diarrhea incidence by 45% (IRR = 0.55, 0.48, 0.61, P < 0.001). Similarly,home-based water treatment reduced by 52% (IRR = 0.48, 0.42, 0.54, P < 0.001). Likewise, a combinationof handwashing with soap and home-based water treatment has reduced childhood diarrhea by 60% (AOR = 0.40, 0.36, 0.47, P < 0.001) after adjusting potential confounders.ConclusionThis study indicated single and combined interventions reduced childhood diarrhea. Promoting these effective or promising intervention effects in rural communities would save many lives of children from diarrhea.Trial registrationRegistered 11 August 2020, http://www.pactr.org/PACTR202008856063947