Background: Colonic endoscopic submucosal dissection (ESD) at “challenging sites” such as the cecum, ascending colon, and colonic flexures could be difficult even for expert endoscopists due to poor endoscope stability/maneuverability, steep angles, and thinner wall thickness. A double-balloon endoluminal intervention platform (EIP) has been introduced in the market to fasten and facilitate ESD, particularly when located at difficult sites. Here, we report our initial experience with an EIP comparing the outcomes of an EIP versus standard ESD (S-ESD) at “challenging sites”. Materials and methods: We retrospectively collected data on consecutive patients with colonic lesions located in the right colon and at flexures who underwent ESD in our tertiary referral center between March 2019 and May 2023. Endoscopic and clinical outcomes (technical success, en bloc resection rate, R0 resection rate, procedure time, time to reach the lesion, and adverse events) and 6-month follow-up outcomes were analyzed. Results: Overall, 139 consecutive patients with lesions located at these challenging sites were enrolled (EIP: 31 and S-ESD: 108). Demographic characteristics did not differ between groups. En bloc resection was achieved in 92.3% and 93.5% of patients, respectively, in the EIP and S-ESD groups. Both groups showed a comparable R0 resection rate (EIP vs. S-ESD: 92.3% vs. 97.2%). In patients undergoing EIP-assisted ESD, the total procedure time was shorter (96.1 [30.6] vs. 113.6 [42.3] minutes, p = 0.01), and the mean size of the resected lesions was smaller (46.2 ± 12.7 vs. 55.7 ± 17.6 mm, p = 0.003). The time to reach the lesion was significantly shorter in the EIP group (1.9 ± 0.3 vs. 8.2 ± 2.7 min, p ≤ 0.01). Procedure speed was comparable between groups (14.9 vs. 16.6 mm2/min, p = 0.29). Lower adverse events were observed in the EIP patients (3.8 vs. 10.2%, p = 0.31). Conclusions: EIP allows results that do not differ from S-ESD in the resection of colorectal superficial neoplasms localized in “challenging sites” in terms of efficacy and safety. EIP reduces the time to reach the lesions and may more safely facilitate endoscopic resection.