Background <p>Endoscopic submucosal dissection (ESD) is a minimally invasive therapy for early gastrointestinal neoplasms, but patients may experience reduced functional capacity and delayed recovery post-procedure. Prehabilitation, has shown benefits in major surgery by improving physical fitness and recovery. We hypothesized that a structured prehabilitation regimen before ESD would enhance postoperative functional recovery and patient outcomes compared to standard care.</p> Methods <p>Single-center, assessor-blinded randomized controlled trial of 100 adults undergoing elective ESD, randomized to 4-week prehabilitation (supervised aerobic/resistance training 3×/week, individualized nutrition with protein supplementation, and psychological support) or usual care (standard instructions without structured exercise or nutrition). The primary outcome was change in six-minute walk distance (6MWD) from baseline to 1 month. Secondary outcomes included handgrip strength, quality of life (SF-36), psychological health (HADS), postoperative complications, length of stay, and 90-day readmissions.</p> Results <p>Baseline characteristics were similar between groups. At 1-month post-ESD, six-minute walk distance had decreased in both groups with no significant between-group difference (mean change from baseline − 40.9&#xa0;m in prehabilitation vs. − 53.3&#xa0;m in controls, <i>p</i> = 0.439). By 3 months, the prehabilitation group surpassed their baseline walking distance (18.9&#xa0;m), whereas controls remained below baseline (− 14.1&#xa0;m), indicating superior functional recovery with prehabilitation (<i>p</i> = 0.022). Prehabilitation also led to greater improvements in early postoperative strength and patient-reported outcomes. At 1 month, handgrip strength increased more in the prehabilitation group (mean 5.6&#xa0;kg vs. 4.1&#xa0;kg, <i>p</i> = 0.001). Anxiety symptoms improved significantly with prehabilitation (HADS anxiety score change − 1.17 vs. − 0.22, <i>p</i> = 0.003), with a parallel significant reduction in depression scores (<i>p</i> = 0.002). Prehabilitation patients reported higher gains in mental quality-of-life by 3 months (SF-36 mental component + 15.4 vs. + 11.4 points, <i>p</i> &lt; 0.001). There were no significant differences in perioperative safety outcomes, average hospital stay, and 90-day readmission rates.</p> Conclusions <p>A 4-week multimodal prehabilitation program for ESD patients significantly improved postoperative functional capacity and psychological well-being without increasing complication rates or hospital stay. Prehabilitation is a safe and effective strategy to enhance recovery and patient-centered outcomes in ESD.</p> Clinical trial registration <p>This trial was retrospectively registered in the Chinese Clinical Trial Registry (ChiCTR) (registration number: ChiCTR2500103062) on May 23, 2025.</p> Level of evidence <p>Level I (Randomized Controlled Trial).</p>