The early diagnosis and prognosis of COVID-19, the disease caused by SARS-CoV-2 infection remain major challenges. Clinical information assessment combined with biomarkers based on molecular changes is of great value in the diagnosis and prognosis of COVID-19. However, the biomarkers for COVID-19 have not been identified. Here, we described the sera proteomic features that could distinguish patients with COVID-19 from healthy patients. In addition, we characterized the serum proteomes of paired samples obtained from 15 patients with COVID-19 during hospitalization and after recovery, as well as samples from the healthy patients, and found several prognostic biomarkers by comparing with published studies, among which 10 were verified by parallel reaction monitoring. Further, we found that the protein changes in sera of COVID-19 patients can reflect in its organ-enriched expression. These findings provide diagnostic biomarkers for COVID-19 and prognostic biomarkers to comprehensively evaluate COVID-19 patient recovery status. Furthermore, our results provide new insights into the pathological changes monitoring by serum changes in COVID-19 patients.