Objective: To explore the effect of stepwise psychological intervention on adverse mood and quality of life of patients after colon cancer surgery. Methods: The clinical data from 102 patients with colon cancer admitted to the Second Hospital of Baoding from January 2018 to June 2022 were collected and analyzed retrospectively. Based on the intervention measures, 51 patients with the general intervention were regarded as the general group, and 51 patients with the stepwise psychological intervention were considered as the intervention group. Piper Fatigue Scale (PFS) was used to scale the degree of Cancer-related fatigue (CRF); Self-rating anxiety scale (SAS) and Self-rating depression scale (SDS) were applied to measure the negative emotion; Positive and negative emotion scale (PANAS) was used to evaluate the degree of positive negative emotions. In addition, Symptom Checklist 90 (SCL-90), Connor-Davidson Resilience Scale (CD-RISC) self-assessment scale, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) were applied to evaluate the mental state, mental resilience, and quality of life, respectively. The adverse reactions, prognosis, and intervention satisfaction after intervention were compared between the two groups. Results: After intervention, the PFS scores, SAS score, SDS score, and PANAS score in the general group and intervention groups were decreased (all P < 0.05), and these scores decreased more obviously in the intervention group compared with the general group (all P < 0.05); The scores of each dimension in SCL-90 scale were decreased in both groups (P < 0.05), and the SCL-90 scores in the intervention group were lower than those in the general group (P < 0.05); The scores of each dimension in CD-RISC scale improved in both groups (P < 0.05), and the scores were higher in the intervention group compared with the general group (P < 0.05); The scores of EORTC QLQ-C30 scale improved in both groups (P < 0.05), and these scores were higher in the intervention groups compared with the general group (P < 0.05). In addition, the adverse reaction rate was lower, while the prognosis and nursing satisfaction were better in the intervention group than those in the general group (all P < 0.05). Logistic regression analysis showed that the poor emotion and poor life quality were the risk factors of the poor prognosis (all P < 0.05). Conclusions: The stepwise psychological intervention can improve the psychological wellbeing and quality of life in the patients after colon cancer surgery.