<p>The management of cancer relies crucially on early diagnosis and personalized treatment. Real-time analysis of tumor markers within the tumor microenvironment via liquid biopsy opens potential pathways for effective cancer treatment and improved survival rates. Detecting low-abundance tumor markers in bodily fluids, particularly during early-stage cancer, poses significant challenges for traditional methods. Electrochemical sensors have emerged as the preferred technology for liquid biopsy. The exceptional multifunctionality of covalent organic frameworks (COFs)—novel crystalline porous organic polymer materials—has led to significant attention in electrochemical sensing; these features include tunable topologies, controllable pore sizes, and strong π-π stacking interactions. Recent advances in COF-based electrochemical sensors for liquid biopsy are summarized here, with details on COF design principles, synthesis and functionalization methods, and electrochemical reaction mechanisms. The focus is on the use of COFs as novel functional materials in electrochemical sensors for detecting tumor markers. Enhancement strategies for COF-based electrochemical sensors are also explored. An in-depth discussion on translating COF-based electrochemical sensors from laboratory achievements into clinical applications is also presented, covering the associated opportunities, challenges, and future research directions. The aim of this review is to offer concise yet profound guidance on the clinical translation of COF-based electrochemical analytical methods, which can contribute to advancing human health and precision diagnostics.</p> Graphical abstract <p></p>