The past decade has witnessed significant advancements in genome-targeted oncology drugs within the realm of precision medicine (PM). However, the cost-effectiveness of oncology PM in a highly populated, low- and middle-income country such as China remains uncertain, particularly due to the absence of systematic reviews conducted in Chinese that address this critical issue. This research protocol outlines a systematic review and meta-analysis aimed at evaluating the cost-effectiveness of genome-targeted anticancer drugs in China.We will perform a comprehensive search on both English-based and Chinese-specific databases, including MEDLINE (Ovid), Embase (Ovid), Chinese Biomedical Literature Database, China National Knowledge Infrastructure, VIP and Wan Fang. The search would be restricted to cost-effectiveness analysis of genome-targeted drugs approved by the National Medical Products Administration of China from 2002 to 2023. Health and economic outcomes will be extracted, and the biases of research will be assessed by the economic evaluations bias checklist. Based on the comparative efficiency research method, we will calculate and pool the net money benefit of genome-targeted oncology drugs relative to usual care using both the random-model and fixed-effect meta-analysis models. Next, meta-regression and jackknife sensitivity analysis will be carried out to identify sources of heterogeneity. In addition, subgroup analyses will be performed according to different cancer types and stages, patient demographics, drug classification and so forth.This study does not involve human or animal subjects, and thus, no ethical approval was required. The findings will be communicated via presentations, conference abstracts and scholarly articles intended for submission to peer-reviewed journals.CRD42024537386.© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.