Objective: The incidence of postoperative complications after percutaneous coronary intervention (PCI) is relatively high, seriously affecting the prognosis of patients. This study explores the application value of the Six Sigma methodology in the preventive management of complications after PCI. Methods: The clinical data of 102 patients who underwent PCI in our hospital from March 2021 to January 2022 were retrospectively analyzed. In accordance with different management methods, these patients were divided into the reference group (n = 49, conventional management method) and the observation group (n = 53, Six Sigma methodology). The anxiety and depression levels, quality of life, cardiac function indexes (left ventricular ejection fraction, left ventricular end-diastolic volume, left ventricular end-systolic volume, and stroke volume), and incidence of complications were compared between the two groups. Results: Before management, no difference was observed in anxiety and depression levels, quality of life, and cardiac function indexes in both groups (p > 0.05). After management, the observation group demonstrated lower anxiety and depression levels, higher quality of life, and lower incidence of complications than the reference group did (p < 0.05), with no significant difference in cardiac function indexes (p > 0.05). Conclusions: The Six Sigma methodology can improve the quality of life and reduce the incidence of postoperative complications, with a high promotion and application value in nursing management after PCI.