This case report describes the successful treatment of pyometra caused by multi-drug resistant (MDR) Klebsiella pneumoniae in a 5-year-old Labrador Retriever. Antibiotic susceptibility testing revealed resistance to commonly used antibiotics, including amoxicillin-clavulanate, gentamicin, and ciprofloxacin, but sensitivity to cefoperazone/sulbactam, a third-generation cephalosporin combined with a beta-lactamase inhibitor. The therapeutic regimen involved cefoperazone/sulbactam in combination with trypsin-chymotrypsin enzyme therapy, aimed at enhancing drug efficacy by facilitating necrotic tissue clearance and promoting resolution of inflammation. This combined treatment led to complete clinical recovery, underscoring its potential as an effective alternative for managing severe open pyometra cases when surgical intervention is contraindicated.