Background Endoscopic resection for large, laterally spreading tumors (LSTs) in the cecum is challenging. Here we report on the clinical outcomes of hybrid endoscopic submucosal dissection (ESD) in large cecal LSTs. Methods We retrospectively reviewed data from patients with cecal LSTs ≥ 2 cm who underwent ESD or hybrid ESD procedures between January of 2008 and June of 2019. We compared the baseline characteristics and clinical outcomes, including procedure time, the en bloc and complete resection rates, and adverse events. Results A total of 62 patients were enrolled in the study. There were 27 patients in the ESD group and 35 patients in the hybrid ESD group, respectively. Hybrid ESD was more used for lesions with submucosal fibrosis. No other significant differences were found in patient characteristics between the two groups. The hybrid ESD group had a significantly shorter procedure time compared with the ESD group (27.60 ± 17.21 vs. 52.63 ± 44.202 min, P = 0.001). The en bloc resection rate (77.1% vs. 81.5%, P = 0.677) and complete resection rate (71.4% vs. 81.5%, P = 0.359) of hybrid ESD were relatively lower than that of the ESD group in despite of no significant difference was found. The perforation and post-procedure bleeding rate (2.9% vs. 3.7%, P = 0.684) were similar between the two groups. One patient perforated during the ESD procedure, which was surgically treated. One patient in the hybrid ESD group experienced post-procedure bleeding, which was successfully treated with endoscopic hemostasis. Post-procedural fever and abdominal pain occurred in six patients in the ESD group and five patients in the hybrid ESD group. One patient in the ESD group experienced recurrence, which was endoscopically resected. Conclusion The results of this study indicate that hybrid ESD may be an alternative resection strategy for large cecal LSTs with submucosal fibrosis.