Background: Mental distress is a mental or psychological syndrome, which influences the health status and treatment effectiveness, getting quality of care in a hospitalized medical surgical inpatient. It is more common in hospital setting than community setting population. Thus, this study aimed to assess the prevalence of mental distress and associated factors among hospitalized medical surgical adult inpatients in public hospitals, Addis Ababa, Ethiopia, 2020.Methods: Institutional based cross-sectional study was conducted with a total of 408 study subjects from March 1-30, 2020. Systematic random sampling technique was used and data was collected using interviewer administered questionnaire. Data was collected by trained nursing students and collected data was entered into Epi-data 3.1 and exported to SPSS version 26 for analysis, and then binary and multiple logistic regressions was performed to check the association between dependent and independent variable.Result: The prevalence of mental distress among hospitalized medical surgical adult inpatients in public hospitals was 53.1% with (95%CI; 48%, 58%). Variables of being married [AOR=2.67; 95%CI(1.065,6.683)], private employee [AOR=2.21; 95%CI(1.001, 4.900)], daily laborer [AOR=4.70; 95%CI(1.218, 18.215)], rural residence [AOR=1.85; 95%CI(1.047,3.264)], taking alcohol [AOR=1.68; 95%CI(1.025, 2.740)], previous psychiatric illness [AOR=3.40; 95%CI(1.078, 10.737)] and co-morbidity [AOR=1.93; 95%CI (1.200, 3.094)] were found to be significantly associated with mental distress; while age, sex, ethnicity, religion, educational status, income, smoking, chat, social support, living condition, history of hospitalization, ward admitted and length of hospital stay were not significantly associated.Conclusion: The prevalence of mental distress was high and being married, private employee, daily laborer, residence in rural area, previous history of psychiatric illness, alcohol used and comorbidity disorder were associated with mental distress among hospitalized adult inpatients. Therefore, health care providers should provide special consideration to those group of patients admitted to the hospital.