Colorectal polyps have few clinical symptoms, and related tumor markers are unclear; therefore, developing a simple and economical tumor detection index for auxiliary diagnosis is necessary. We aimed to investigate differences in salivary and fecal microbiota, inflammation-related indicators, serum lipid indices, and tumor markers between patients with colorectal polyps and healthy controls, to identify novel non-invasive biomarkers for colorectal polyps. This case-control study enrolled 47 patients with colorectal polyps and 59 age- and sex-matched healthy controls between 13 May 2022 and 20 November 2023. From each participant, we collected salivary and fecal samples, fasting venous blood samples, polyp tissues, and normal intestinal tissues. We then evaluated the diagnostic performance of multiple markers, including salivary and fecal microbiota, routine blood tests, blood lipids, serum tumor markers, and the NOD-like receptor protein 3 (NLRP3) inflammasome, both individually and in combination. The assessment was based on metrics such as the Youden index, sensitivity, and specificity. There were statistically significant differences in several markers between patients and controls. The receiver operating characteristic curve analysis showed that the areas under the curve for the diagnosis of colorectal polyps using the individual and combined detection of the neutrophil-to-lymphocyte ratio, mean corpuscular haemoglobin (MCH), MCH concentration, cystatin C, triglycerides, low-density lipoprotein cholesterol, carcinoembryonic antigen, , , , , , and were 0.696, 0.726, 0.742, 0.771, 0.829, 0.731, 0.785, 0.759, 0.738, 0.786, 0.739, 0.764, 0.757, and 0.996, respectively. Combining 13 markers was better than a single marker regarding the diagnostic effect. Compared to that in normal mucosal tissues, the ratio of positively stained areas for NLRP3, apoptosis-associated speck-like proteins containing a caspase recruitment domain, and interleukin-1β was higher in polyp tissues. Detection of salivary and fecal microbiota, multiple inflammation-related indicators, serum lipid indices, and tumor markers can non-invasively and effectively improve the diagnosis of colorectal polyps.