Abstract Background Enterococcal bacteremia has become prevalent in the recent decade, especially in hospitalized patients. Moreover, the rise in resistance patterns against antibiotic drugs regarding enterococci infection, such as cephalosporins, ampicillin and vancomycin, is prevailing. The major driving force behind this is the incongruous use of antibiotics with a minor contribution from environmental stressors which calls for vigilant and prudent administration of evidence-based antibiotics. Methods A retrospective study was conducted from January 1 2017 until December 31 2021, at the tertiary care center, Dr Ziauddin Hospital in Karachi, Pakistan. Results Our research revealed ampicillin resistance in 87 (63.5%), with an estimated 25 (18.8%) mortality. Male gender 19 (76%) and vancomycin resistance 13 (52%) were associated with increased mortality. Furthermore, appropriate antibiotic therapy reduced the risk of death compared with inappropriate and excessive use of antibiotics 10 (40%) vs. 15 (60%) vs. 20 (80%) respectively. Targeted therapy with amoxicillin/clavulanic acid was associated with lower mortality 1 (4%) and higher discharge rates 34 (32.1%). On Kaplan-Meier survival, targeted therapy with amoxicillin/clavulanic acid was associated with shorter hospital stays and prolonged survival. UTI was found as the most common source of enterococcal bacteremia 57 (41.6%), followed by respiratory 21 (15.3%) and intra-abdominal 13 (9.5%). In 26 (19%) patients, no identifiable source of infection was found. Conclusion Vancomycin resistance and male gender were found independent risk factors for mortality. The use of inappropriate antibiotics significantly increases mortality in these patients. The appropriate antibiotic therapy reduces the risk of death. Furthermore, overuse of antibiotics didn’t reduce mortality; instead increased the financial burden and chances of developing multi-drug resistant strains of other organisms by increasing hospital stays of patients.