School-based deworming program is implemented to control and eliminate Schistosoma mansoni infection in many endemic countries, including Ethiopia. However, pre-school-age children (pre-SAC) are not targeted to receive preventive chemotherapy against S. mansoni infection, partly due to a lack of information on the disease burden. We assessed the prevalence and correlates of S. mansoni infection among pre-SAC in Southern Ethiopia. A total of 1683 pre-SAC aged 4 to 7 years were screened for S. mansoni infection. A multilevel binary logistic regression was fitted to detect the significant determinants of S. mansoni infection. Adjusted odds ratios (AORs) with a 95% confidence interval (CI) were used to identify determinants of S. mansoni infection. The overall prevalence of S. mansoni infection was 14.3% (95% CI: 12.6, 16.0%). S. mansoni infection was significantly higher among 6-year-old (AOR = 2.58, 95% CI: 1.55, 4.27) and 7-year-old children (AOR = 4.63, 95% CI: 2.82, 7.62). Accompanying others to water sources sometimes (AOR = 2.60, 95% CI: 1.12, 6.01) and all the time (AOR = 5.91, 95% CI: 2.51, 13.90), and residing in less than one kilometer from the infested water source (AOR = 3.17, 95% CI: 1.47, 6.83) increased the odds of S. mansoni infection. In conclusion, the prevalence of S. mansoni infection among pre-SAC in the study area was moderate. The study highlights the urgent need to include pre-SAC aged 4 to 7 years in annual preventive chemotherapy campaigns to reduce the risk of possible sources of infection and enhance the achievement of the elimination target.