Objective: To systematically evaluate the current status of psychological distress among patients with malignant tumors during chemotherapy and analyze its multi‑dimensional influencing factors. Methods: Evidence from domestic and international cross‑sectional and longitudinal studies over the past decade was integrated. Evidence was reviewed hierarchically from individual, disease‑treatment, and social‑environmental perspectives, and a multi‑factor path model was constructed. Results: The incidence of severe psychological distress during chemotherapy ranged from 20% to 35%. Independent risk factors included low economic status, high grade of treatment‑related side effects, metastatic disease, and low social support. Fatigue and sleep disturbance exerted significant mediating effects between treatment‑related factors and psychological distress. Moreover, economic hardship and deficient family support showed synergistic amplifying effects. Conclusion: Psychological distress is driven by multi‑factor interactions. The fatigue‑sleep disturbance mediating chain and social buffering system constitute key intervention targets. A “two‑step screening and three‑tier intervention” system is recommended. Psychological distress management should be valued equally with somatic treatment to improve the effectiveness of integrated care.