BACKGROUND: Prompt detection of colorectal cancer (CRC) among individuals younger than age 50 years (early-onset CRC) is a clinical priority because of its alarming rise. METHODS: We conducted a matched case-control study of 5075 incident early-onset CRC among US commercial insurance beneficiaries (113 million adults aged 18-64 years) with 2 or more years of continuous enrollment (2006-2015) to identify red-flag signs and symptoms between 3 months to 2 years before the index date among 17 prespecified signs and symptoms. We assessed diagnostic intervals according to the presence of these signs and symptoms before and within 3 months of diagnosis. RESULTS: Between 3 months and 2 years before the index date, 4 red-flag signs and symptoms (abdominal pain, rectal bleeding, diarrhea, and iron deficiency anemia) were associated with an increased risk of early-onset CRC, with odds ratios (ORs) ranging from 1.34 to 5.13. Having 1, 2, or at least 3 of these signs and symptoms were associated with a 1.94-fold (95% confidence interval [CI] = 1.76 to 2.14), 3.59-fold (95% CI = 2.89 to 4.44), and 6.52-fold (95% CI = 3.78 to 11.23) risk (Ptrend < .001), respectively, with stronger associations for younger ages (Pinteraction < .001) and rectal cancer (Pheterogenity = .012). The number of different signs and symptoms was predictive of early-onset CRC beginning 18 months before diagnosis. Approximately 19.3% of patients had their first sign or symptom occur between 3 months and 2 years before diagnosis (median diagnostic interval = 8.7 months), and approximately 49.3% had the first sign or symptom within 3 months of diagnosis (median diagnostic interval = 0.53 month). CONCLUSIONS: Early recognition of red-flag signs and symptoms (abdominal pain, rectal bleeding, diarrhea, and iron-deficiency anemia) may improve early detection and timely diagnosis of early-onset CRC.