Multidrug-resistant (MDR) sepsis is a critical global health challenge, with 48.9 million cases and 11 million deaths annually. The rise of MDR organisms has increased the urgency of managing MDR sepsis, which is associated with high mortality, multi-organ failure, and immune paralysis. Factors contributing to recurrent sepsis include aging, antibiotic overuse, inadequate antibiotic therapy, and comorbidities. MDR sepsis is linked to increased readmission rates and cognitive and organ dysfunction, raising healthcare costs. Innovative diagnostic methods like point-of-care testing (POCT) and molecular techniques (e.g., MALDI-TOF MS) are being explored for rapid detection, but they are limited in identifying resistance markers. Combination therapy and precision therapy are being used to treat MDR sepsis, but challenges remain in diagnosing and treating it effectively. MDR sepsis is a growing burden globally, with significant economic costs, particularly in the U.S. and India. The pathogenesis of sepsis involves complex immune responses, leading to inflammation and immunosuppression. MDR pathogens like MRSA, CRE, and P. aeruginosa complicate treatment. The development of antibiotic resistance is a major challenge, with bacteria evolving new resistance mechanisms. Rational antibiotic use is essential to reduce resistance and improve outcomes. Diagnostic challenges include the limitations of traditional blood cultures, which are slow and may miss pathogens. Biomarkers like PCT and CRP are used for early detection, but they have limited specificity. Advanced techniques like SERS and MALDI-TOF MS offer faster diagnosis but are not yet fully effective for resistance detection. Addressing MDR sepsis requires improved diagnostics, targeted therapies, and regional strategies to manage resistance patterns.Multidrug-resistant (MDR) sepsis is a critical global health challenge, with 48.9 million cases and 11 million deaths annually. The rise of MDR organisms has increased the urgency of managing MDR sepsis, which is associated with high mortality, multi-organ failure, and immune paralysis. Factors contributing to recurrent sepsis include aging, antibiotic overuse, inadequate antibiotic therapy, and comorbidities. MDR sepsis is linked to increased readmission rates and cognitive and organ dysfunction, raising healthcare costs. Innovative diagnostic methods like point-of-care testing (POCT) and molecular techniques (e.g., MALDI-TOF MS) are being explored for rapid detection, but they are limited in identifying resistance markers. Combination therapy and precision therapy are being used to treat MDR sepsis, but challenges remain in diagnosing and treating it effectively. MDR sepsis is a growing burden globally, with significant economic costs, particularly in the U.S. and India. The pathogenesis of sepsis involves complex immune responses, leading to inflammation and immunosuppression. MDR pathogens like MRSA, CRE, and P. aeruginosa complicate treatment. The development of antibiotic resistance is a major challenge, with bacteria evolving new resistance mechanisms. Rational antibiotic use is essential to reduce resistance and improve outcomes. Diagnostic challenges include the limitations of traditional blood cultures, which are slow and may miss pathogens. Biomarkers like PCT and CRP are used for early detection, but they have limited specificity. Advanced techniques like SERS and MALDI-TOF MS offer faster diagnosis but are not yet fully effective for resistance detection. Addressing MDR sepsis requires improved diagnostics, targeted therapies, and regional strategies to manage resistance patterns.