Patients not only experience symptoms caused by cancer but also suffer from the accompanying psychological pain. Therefore, these patients do not have high quality of life. According to the World Health Organization, the incidence of leukemia in China in 2020 was 5.1/100000, the mortality rate was 3.3/100000, and the prevalence rate was 16.7/100000. Therefore, it is important to examine the influence of comorbid subthreshold depressive symptoms on leukemia patients. To determine the impact of comorbid subthreshold depressive symptoms on cancer-related fatigue and complications in leukemia patients, thereby providing a basis for early diagnosis and treatment in clinical practice. A questionnaire survey was conducted among leukemia patients admitted to a tertiary hospital in Xi'an, Shaanxi Province, China, from August 2022 to December 2023. Patients with a score > 16 on the Chinese Classification of Mental Disorders (CCMD-3) and a Hamilton Depression Rating Scale score of 8-17 were classified as the subthreshold depressive group (n = 95), while 100 leukemia patients admitted during the same period were classified as the control group. Data were collected using Epidata 3.1 software, and comparisons were made between the two groups regarding general clinical data, the Piper Fatigue Scale (PFS), the Pittsburgh Sleep Quality Index (PSQI), the Numeric Rating Scale for pain assessment, laboratory indicators, and the occurrence of complications. In this survey, 120 leukemia patients with depression were preliminarily screened, 95 patients with subthreshold depression were ultimately selected as the subthreshold depression group, and 100 leukemia patients admitted during the same period were enrolled as the normal group. Comparison of basic clinical data between the two groups revealed no significant differences in age, sex, body mass index, cognitive function, or comorbidity with other chronic diseases. However, there were statistically significant differences in the use of radiotherapy and regular exercise between the two groups (P < 0.05). Comparisons of scales and laboratory indicators revealed no significant differences in albumin or PSQI scores between the two groups, but there were statistically significant differences in pain scores, PSQI scores, PFS scores, hemoglobin levels, and C-reactive protein levels (P < 0.05). Spearman's correlation analysis indicated that cancer-related fatigue was correlated with age, hemoglobin levels, C-reactive protein levels, pain, and regular exercise among leukemia patients with subthreshold depression. Multivariate regression analysis revealed that advanced age, combined radiotherapy, pain, and low hemoglobin levels were risk factors for cancer-related fatigue in leukemia patients with comorbid subthreshold depression, while regular exercise was a protective factor against cancer-related fatigue. Follow-up comparisons revealed a significantly lower overall incidence of complications in the control group (4%) than in the depressive group (24.21%; P < 0.001). Leukemia patients with comorbid subthreshold depressive symptoms experience more severe cancer-related fatigue and a higher incidence of complications. These findings may be related to advanced age, combined radiotherapy, pain, and low hemoglobin levels, while regular exercise may effectively alleviate symptoms.