Background: In recent years, the morbidity and mortality of cancer patients have continued to increase in China, and there is an urgent need to develop an effective method to monitor tumor dynamics and measure tumor burden. Derived from the cell-free fraction of blood in cancer patients, circulating tumor DNA (ctDNA) has been regarded as a promising surrogate for tumor tissue biopsies. With the development of sequencing technology, ctDNA has been recognized as a specific and highly sensitive biomarker, and it has become a hot research spot in recent years. Methods: In this paper, we investigated clonal changes before and after surgery in liver cancer patients using ctDNA. Results: First, we evaluated the accuracy and stability of the method in ctDNA detection using virtual tumor samples with known mutations. The results showed that our method detected variants with an allelic frequency of at least 0.5%. We then applied this method to 34 liver cancer patients. A total of 266 clinically relevant mutations were identified in the pretreatment plasma samples. Through the analysis of plasma DNA samples at different treatment time points, we also investigated the possibility of using ctDNA as a prognostic factor to reflect tumor dynamics and to evaluate clinical responses. Conclusions: The results demonstrated that targeted high-depth next-generation sequencing can be used in ctDNA detection. Compared to traditional biopsy, the detection of ctDNA provides more information for human liver cancer, which is essential to guide the selection of therapy and predict prognosis.