INTRODUCTION: Cardiovascular disease (CVD) represents a significant health and economic burden in China. Despite extensive research on CVD management in primary care, the cost-effectiveness of current practices remains suboptimal. The overall aim of this study is to test the efficacy of an integrated, cost-effectiveness-oriented management (CEOM) intervention to improve CVD risk and harm management in primary healthcare settings in Anhui, China. METHODS AND ANALYSIS: This open-label, multi-centre, cluster-randomised controlled trial will be conducted in 32 village clinics in Anhui Province, China. Clinics will be randomised (1:1) to the CEOM intervention or usual care. The CEOM intervention integrates a prospective cost-effectiveness analysis from a societal perspective into the clinical workflow. It assesses patient eligibility and prioritises intervention themes and specific items based on predicted incremental cost-effectiveness ratios (ICER), guiding clinicians to deliver tailored management procedures. Implementation is supported by standardised training, automated performance feedback and peer support. Participants (n=1920) are permanent residents aged ≥35 years with diagnosed hypertension, diabetes and/or CVD. The primary outcome is the ICER, using Quality-Adjusted Life Years (QALYs) as the primary effect measure. The ICER will be evaluated based on cumulative QALYs and direct and indirect costs assessed at 12 and 24 months. Secondary outcomes include changes in knowledge, attitudes and practices, major adverse cardiovascular events, QALYs as estimated using the EQ-5D-5L ratings and direct and indirect costs. Data will be analysed using linear mixed models and generalised estimating equations following intention-to-treat principle. ETHICS AND DISSEMINATION: The study was approved by the Medical Ethics Committee of Anhui Medical University (83230358). Results will be disseminated via peer-reviewed journals, conferences and policy briefs. TRIAL REGISTRATION NUMBER: ISRCTN registry, ISRCTN87887485. Registered on 28 January 2026.