Lung cancer is prevalent worldwide. Antiangiogenic therapy is an important treatment strategy for patients with advanced or recurrent non-small cell lung cancer (NSCLC). Currently, there is still a lack of reliable markers for efficacy testing and evaluation of antiangiogenic efficacy. We used label-free quantitative proteomics technology to read a total of 516 proteins in the plasma proteome of advanced NSCLC and the control group. Compared with the control group, 83 proteins were significantly differentially expressed in NSCLC. Bioinformatics analysis methods were used to analyze the biological significance of differentially expressed proteins. In conjunction with clinical data, the efficacy of antiangiogenic inhibitors was analyzed. There were 20 protein expression differences in the effective antiangiogenic treatment group compared with the control group. It was found that SERPINF1 was downregulated in newly diagnosed NSCLC compared with the control group, but upregulated in the effective antiangiogenic treatment group, and the NSCLC single cell atlas showed that SERPINF1 was highly expressed in fibroblasts. The study revealed the serum proteomic profile of Advanced NSCLC and explored efficacy markers of antiangiogenic drugs.