Earlier detection of colorectal cancer (CRC) results in improved survival. Existing non-invasive biomarkers have suboptimal accuracy. Neurotensin (NTS) is involved in CRC carcinogenesis. This study evaluated the diagnostic potential of plasma NTS for colorectal polyps and cancers. Participants were selected based on national CRC referral guidelines. All subjects underwent colonoscopy. Average plasma concentrations were compared across different diagnostic groups. Predictors for detecting colorectal neoplasia were identified. Receiver operator characteristic (ROC) curve analysis assessed the diagnostic accuracy of NTS. An independent biobank was used as validation group. Of 165 participants, 46 had polyps or CRC. Significantly higher plasma NTS was found in the colonic neoplasia group (603.6 pg/ml vs. 407.2 pg/ml, p < 0.01). Risk factors for colonic polyps or cancers included Loge (plasma NTS concentration) (OR, 2.73; 95% CI, 1.33–5.59, p < 0.01), loge (Age) (OR, 15.49; 95% CI, 2.67–89.66, p < 0.01) and cigarette smoking (OR, 3.49; 95% CI, 1.31–9.26, p = 0.01). Plasma NTS had an optimal sensitivity of 60.4% and specificity of 71.6% for the diagnosis of colorectal polyps and cancers. Similar diagnostic accuracy was obtained in the validation group. Plasma NTS has the potential to be a non-invasive biomarker for colorectal neoplasia. It appears to be more accurate than existing blood markers and is unique in being able to detect precancerous polyps.