Background: Debridement is essential for successful wound management. Enzymatic debridement is commonly utilized in wound care but has been reported to be unsafe in wounds with significant bacterial bioburden, unless used in conjunction with topical antimicrobials. We examine this hypothesis with 2 commercially available, commonly used preparations of enzymatic debriding agents. Materials and Methods: Using a standard rodent model of a chronically infected granulating wound with bacterial levels greater than 1 × 10⁵ Colony Forming Units per gram of tissue, commercially available preparations of collagenase and papain-urea were utilized to investigate the response of infected wounds to these preparations, and to evaluate their ability to overcome the inhibition of infection on wound healing. Quantitative bacteriology of tissue biopsies and wound healing trajectories were used to compare the preparations to saline-treated negative controls. Results: Collagenase- and papain-urea-treated wounds demonstrated a reduction in bacterial burden of wounds to < 10⁵ colony forming units/gram of tissue (P < .05). This decrease in bacterial bioburden occurred rapidly, allowing wounds to achieve bacterial balance in a short period of time. Wounds treated with enzymatic debriding agents healed significantly faster and to greater extent than saline-treated controls (P < .01); a direct reflection of the decreasing bacterial load of the wound. Conclusions: Collagenase and papain-urea appear beneficial and safe even in wounds with high bacterial loads, and appear to significantly aid extent and rate of healing, probably by lowering bacterial burden through their positive enzymatic actions on bacteria and necrotic tissue.