To overcome the dependency of strategies utilizing cell‐free DNA (cfDNA) on tissue sampling, the emergence of sequencing panels for non‐invasive mutation screening was promoted. However, cfDNA sequencing with panels still suffers from either inaccuracy or omission, and novel approaches for accurately screening tumor mutations solely based on plasma without gene panel restriction are urgently needed. We performed unique molecular identifier (UMI) target sequencing on plasma samples and peripheral blood mononuclear cells (PBMCs) from 85 hepatocellular carcinoma (HCC) patients receiving surgical resection, which were divided into an exploration dataset (20 patients) or an evaluation dataset (65 patients). Plasma mutations were identified in pre‐operative plasma, and the mutation variant frequency change (MVFC) between post‐ and pre‐operative plasma was then calculated. In the exploration dataset, we observed that plasma mutations with MVFC