Sepsis is a critical healthcare challenge, causing 48.9 million cases and 11 million deaths annually, with an economic burden of USD 38 billion in the United States. The rise of multidrug-resistant organisms (MDROs) has heightened the urgency of managing multidrug-resistant (MDR) sepsis, a global health concern. This review provides an overview of the epidemiology and healthcare challenges associated with MDR sepsis, particularly in critically ill hospitalized patients. Key findings highlight the complex pathophysiology and immune responses in MDR sepsis, which significantly hinder treatment. Factors contributing to recurrent sepsis include aging, antibiotic overuse, inadequate empirical antibiotic therapy, and underlying comorbidities. Studies show a correlation between elevated readmission rates and cognitive and organ dysfunction, increasing hospital-associated costs. Innovative diagnostic methods, such as point-of-care testing (POCT) devices, are being developed to detect sepsis rapidly and accurately. Treatment interventions include combination therapy with antibiotics from different classes and personalized precision therapy. Addressing MDR sepsis at regional levels based on local pathogen resistance patterns is crucial for effective treatment and minimizing adverse effects. The review also discusses the pathogenesis and mechanisms of drug resistance, common pathogens involved in MDR sepsis, diagnostic challenges and innovations, and clinical management strategies.Sepsis is a critical healthcare challenge, causing 48.9 million cases and 11 million deaths annually, with an economic burden of USD 38 billion in the United States. The rise of multidrug-resistant organisms (MDROs) has heightened the urgency of managing multidrug-resistant (MDR) sepsis, a global health concern. This review provides an overview of the epidemiology and healthcare challenges associated with MDR sepsis, particularly in critically ill hospitalized patients. Key findings highlight the complex pathophysiology and immune responses in MDR sepsis, which significantly hinder treatment. Factors contributing to recurrent sepsis include aging, antibiotic overuse, inadequate empirical antibiotic therapy, and underlying comorbidities. Studies show a correlation between elevated readmission rates and cognitive and organ dysfunction, increasing hospital-associated costs. Innovative diagnostic methods, such as point-of-care testing (POCT) devices, are being developed to detect sepsis rapidly and accurately. Treatment interventions include combination therapy with antibiotics from different classes and personalized precision therapy. Addressing MDR sepsis at regional levels based on local pathogen resistance patterns is crucial for effective treatment and minimizing adverse effects. The review also discusses the pathogenesis and mechanisms of drug resistance, common pathogens involved in MDR sepsis, diagnostic challenges and innovations, and clinical management strategies.