Objective: The current investigation aims to assess the effectiveness and practical worth of a combined treatment approach that incorporates sertraline and computer-assisted cognitive behavioral therapy (CCBT) for individuals experiencing depression subsequent to schizophrenia. Methods: The research methodology involved the selection of 68 participants who were diagnosed with post-schizophrenia depression and were receiving care at our institution between April 2023 and May 2024. These individuals were allocated into two distinct cohorts—the control group, consisting of 34 individuals, and the experimental group, also comprising 34 individuals—through the application of a random number generator. Both groups received antipsychotic medication plus sertraline, while the observation group additionally received CCBT. Clinical symptoms, cognitive function, self-care abilities, quality of life improvement, and adverse reaction rates were observed and compared between the two groups at specific time points. Results: At the 4th, 8th, and 12th weeks of treatment, the CDSS scores in the observation group were significantly higher than those in the control group, and the overall effective clinical treatment rate was also higher in the observation group (P<0.05). Comparing MCCB and ADL scores at the 4th, 8th, and 12th weeks, the observation group scored higher than the control group (P<0.05). Post-treatment comparisons of SF-36 scores showed the observation group to be superior (P<0.05). The overall incidence of adverse reactions was lower in the observation group than in the control group (P<0.05). Conclusion: In patients with post-schizophrenia depression, the combination of sertraline and CCBT can effectively improve symptom alleviation and overall treatment efficacy, enhance cognitive function and self-care abilities, and contribute to the betterment of patients' quality of life.