Objective: To investigate the diagnostic value of serum fibrin degradation complex (DR-70) combined with carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199) in colorectal cancer. Methods: A total of 200 patients with colorectal cancer admitted to Fuyang Fifth People’s Hospital from January 2019 to June 2021 were selected, and 100 patients with benign colorectal lesions and 100 healthy subjects were selected. Serum DR-70, CEA and CA199 levels were detected. The serum levels of DR-70, CEA and CA199 in each group were compared, and the diagnostic efficacy of each index for colorectal cancer was evaluated by receiver operating characteristic curve (ROC). The relationship between DR-70 and clinicopathological parameters of colorectal cancer was analyzed, and the changes of serum DR-70 levels before and after surgery in patients with colorectal cancer were observed. Results: The serum DR-70 level in patients with colorectal cancer was (1.15±0.39) μg/mL, which was higher than (0.47±0.10) μg/mL in patients with benign colorectal lesions and (0.46±0.12) μg/mL in healthy subjects, and the differences were statistically significant (P<0.05). The serum CEA and CA199 in patients with colorectal cancer were also significantly increased (P<0.05). ROC curve analysis showed that the area under the curve of DR-70, CEA and CA199 in the diagnosis of colorectal cancer was 0.838, 0.805 and 0.622, respectively. The area under the curve of the combined diagnosis of the three was 0.919, which was better than that of the single detection (P<0.05). In patients with colorectal cancer, the serum DR-70 level in stage III+IV patients was significantly higher than that in stage I+II patients, and the serum DR-70 level in patients with low differentiation was significantly higher than that in patients with medium and high differentiation (P<0.05). The postoperative serum DR-70 level in patients with colorectal cancer was lower than that before operation, and the difference was statistically significant (P<0.05). Conclusion: The serum level of DR-70 in patients with colorectal cancer is significantly increased. DR-70 can be used as a potential marker for colorectal cancer screening, and combined with CEA and CA199 can improve the diagnostic efficacy.