Introduction. Invoked by the presence of biofilm, upregulation of tissue-destroying proteases is the hallmark of continuous inflammation in nonhealing wounds. Preventing biofilm re-formation and quenching protease activity in the wound bed, followed by providing regenerative factors to the area may aid in triggering a wound healing trajectory. Objective. In this case series, the author evaluated a multimodal approach in patients with wounds that did not respond to conventional therapy. These patients were initially treated with purified native cross-linked extracellular matrix (ECM) with polyhexamethylene biguanide (PHMB) antimicrobial barrier (PCMP) followed by placental allografts. Materials and Methods. Wounds underwent once-weekly debridements, followed by application of PCMP and subsequent applications of hypothermically stored amniotic membrane (HSAM) and/or dehydrated amnion/chorion membrane (dACM) placental allografts. Results. Sixteen wounds were included in the study, but 1 patient died before healing rates were calculated. Of the remaining 15 wounds, 13 (86.67%) closed at or before week 12, with the remaining 2 wounds achieving complete wound closure by week 17. A subgroup analysis of larger wounds (> 25 cm2) also was conducted. Of the 16 wounds, 6 (37.5%) were present for 8.5 weeks; these wounds ranged in size from 31 cm2 to 78 cm2, with mean baseline area (standard deviation) of 43.5 cm2 (15.99) and median baseline area of 42 cm2. Of the 5 larger wounds, 3 (60%) closed before 12 weeks. All wounds achieved complete wound closure by week 17 following application of PCMP and subsequent application of HSAM or dACM. Conclusions. Applications of PCMP to nonhealing wounds, followed by application of dACM or HSAM placental allograft, in conjunction with the standard of care provided at the author’s institution, resulted in satisfactory wound closure rates in a diverse group of wounds in a patient group with multiple comorbidities.