ObjectiveThis study investigated the correlation between uncertainty stress (US) and depression among healthcare professionals (HCPs) in China.Design, settings and participantsA cross-sectional online survey was conducted by recruiting HCPs from three provinces in China (central, eastern and western) through purposive sampling between 29 September 2022 and 18 January 2023. US was measured using the Life Stress Questionnaire and depression was measured using the Patient Health Questionnaire-9. In total, 2976 questionnaires were deemed valid.Primary and secondary outcomeThis study examined the prevalence of US and depression among HCPs in China; the correlating sociodemographic traits; and the correlation between US and depression.ResultsThe prevalence of US and depression among HCPs in China was 26.54% (790 out of 2976) and 71.63% (2132 out of 2976). Binary logistic analysis revealed that individuals with graduate degrees (OR: 1.83; 95% CI 1.07 to 3.11; p<0.05), central China (OR: 1.75; 95% CI 1.36 to 2.24; p<0.01), primary medical institutes (OR: 1.33; 95% CI 1.03 to 1.72; p<0.05), secondary medical institutes (OR: 1.30; 95% CI 1.01 to 1.68; p<0.05), an annual income of less than ¥50 000 (OR: 1.85; 95% CI 1.26 to 2.73; p<0.01) and an income range of ¥50 000–¥99 999 (OR: 1.49; 95% CI 1.10 to 2.03; p<0.05) were associated with a higher likelihood of US. The adjusted logistic regression model demonstrated that HCPs with higher US had a greater likelihood of depression (adjusted OR: 5.02; 95% CI 3.88 to 6.50; p<0.01). The increase in the US score was paralleled by an increased depression score (beta (B): 1.32; 95% CI 1.25 to 1.39; p<0.01).ConclusionThese findings reveal a significant correlation between US and depression among HCPs and suggest that improving the management of US may help reduce the prevalence of depression among HCPs.