Background: Excluding skin cancers, colorectal cancer is the third most common cancer diagnosed in both men and women in the United States. Colorectal cancer (CRC) affects men and women of all racial and ethnic groups and is most often found in people who are 50 years old or older. To aid diagnosis and improve screening for CRC, this study focuses on identifying glycoprotein biomarkers using blood serum. Methods: Novel methods including liquid-chromatography/mass-spectrometry (LC-MS) with in-house peak integration software PB-Net were used to identify glycoprotein biomarkers by analyzing blood serum. Samples were sourced from different biorepositories including 245 CRC, 38 adenoma and 196 healthy controls. The data were split into 75% training and 25% hold-out test set for multivariable predictions. Statistical analysis was performed on normalized data to identify potential biomarkers differentiating adenoma and different stages of CRC samples from the healthy controls. Results: There were 419 significantly differentially expressed glycopeptides/peptides from comparisons between CRC and adenoma samples against the healthy control samples with an FDR < 0.05. A subset of these biomarkers were assessed, generating a 21-biomarker multivariable classifier model. We observed a test set AUC of 0.926, and the sensitivity for all stages of CRC was 90% (87% early stage, 92% late stage). Notably, sensitivity for adenomas was 79%, a large improvement upon the state of the art in adenoma diagnosis. Conclusions: Identification of these key glycopeptides/peptides in blood serum could prove to be a promising non-invasive diagnostic tool that can help improve screening and aid in early detection of advanced adenomas and CRC.