Background: Biomimetic matrix (BMM) is a fully synthetic matrix composed of self-assembling peptides, an emerging class of biomaterials, for the treatment of chronic wounds. Aim: This preliminary case series explores the potential clinical applications of BMM in eight patients with chronic diabetic foot ulcers. The patients were selected based on wound chronicity and a lack of response to standard of care and/or previous treatments with biologics, including amniotic-derived materials, decellularized collagen, and living cell/collagen-derived products. Results: A total of eight subjects were evaluated and monitored in this case series. All subjects had diabetes, and the comorbidities included venous stasis, Charcot neuroarthropathy, obesity, osteomyelitis, peripheral vascular disease, and a history of prior partial foot amputation. All subjects treated with BMM responded after one to three applications. Overall, treatment with BMM resulted in an average percent wound area reduction of 63.6% over 6 weeks for chronic wounds that had remained open for an average of 21.5 months. Conclusion: BMM treatment reduced the wound area and depth of complex, stalled chronic diabetic lower extremity wounds. Relevance for patients: BMM, a synthetic self-assembling peptide-based matrix, demonstrated progression in treating stalled diabetic wounds that were not responsive to human- or animal-derived products.