Background: We previously reported that nonsteroidal anti-inflammatory drugs (NSAIDs) induced small intestinal damage through nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-dependent interleukin-1β secretion in mice. Our further study demonstrated that colchicine, a therapeutic agent for gout, significantly suppressed NSAID-induced small intestinal damage by inhibiting NLRP3 inflammasome activation in mice. However, clinical efficacy of colchicine for NSAID-induced small intestinal damage has not been established. Objectives: We examined the clinical efficacy of colchicine in patients with NSAID-induced severe small intestinal damage as an animal-to-human translational research. Methods: This is a single-center, single-arm, prospective pilot study. From February 2017 to March 2019, we performed video capsule endoscopy (VCE) to screen 10 patients who took NSAIDs continuously for more than 3 months, and 7 of those with severe small intestinal damage were enrolled. Participants were treated with oral colchicine 0.5 mg twice daily for 8 weeks and thereafter followed up with blood tests and VCE. Results: After 8 weeks of colchicine treatment, complete healing was achieved in 4 patients (57.1%), and the median number of small erosions decreased significantly from 7.0 (range, 5.0–10.5) to 0.0 (range, 0.0–2.3) (p = 0.031). One patient withdrew due to diarrhea, and 5 patients revealed slightly elevated liver enzymes during the study. No other adverse events including changes in blood tests and clinical symptoms were observed. Conclusions: Colchicine treatment achieved a high rate of complete healing in patients with NSAID-induced severe small intestinal damage.