BACKGROUND: Colorectal laterally spreading tumors (LSTs) are best treated with endoscopic submucosal dissection or endoscopic mucosal resection. AIM: To analyze the clinicopathological and endoscopic profiles of colorectal LSTs, determine predictive factors for high-grade dysplasia (HGD)/carcinoma (CA), submucosal invasion, and complications. METHODS: We retrospectively assessed the endoscopic and histological characteristics of 375 colorectal LSTs at our hospital between January 2016 and December 2023. We performed univariate and multivariate analysis to identify risk factors associated with HGD/CA, submucosal invasion and complications. RESULTS: The numbers of granular (LST-G) and non-granular LST (LST-NG) were 260 and 115, respectively. The rates of low-grade dysplasia and HGD/CA were 60.3% and 39.7%, respectively. Multivariate analysis indicated that a tumor size ≥ 30 mm [odds ratio (OR) = 1.934, = 0.032], LST granular nodular mixed type (OR = 2.100, = 0.005), and LST non-granular pseudo depressed type (NG-PD) (OR = 3.016, = 0.015) were independent risk factors significantly associated with higher odds of HGD/CA. NG-PD (OR = 6.506, = 0.001), tumor size (20-29 mm) (OR = 2.631, = 0.036) and tumor size ≥ 30 mm (OR = 3.449, = 0.016) were associated with increased odds of submucosal invasion. Tumor size ≥ 30 mm (OR = 4.888, = 0.003) was a particularly important predictor of complications. A nomogram model demonstrated a satisfactory fit, with an area under the receiver operating characteristic curve of 0.716 (95% confidence interval: 0.653-0.780), indicating strong predictive performance. CONCLUSION: The novel nomogram incorporating tumor size, location, and morphology predicted HGD/CA during endoscopic resection for LSTs. NG-PD lesions larger than 20 mm were more likely to invade the submucosa. Tumor size ≥ 30 mm was an important predictor of complications.