Bacterial antibiotic resistance (AMR) is a significant threat to public health, with the sentinel ‘ESKAPEE’ pathogens, being of particular concern. A cohort study spanning 5.5 years (2016–2021) was conducted at a provincial general hospital in Crete, Greece, to describe the epidemiology of ESKAPEE-associated bacteraemia regarding levels of AMR and their impact on patient outcomes. In total, 239 bloodstream isolates were examined from 226 patients (0.7% of 32 996 admissions) with a median age of 75 years, 28% of whom had severe comorbidity and 46% with prior stay in ICU. Multidrug resistance (MDR) was lowest for Pseudomonas aeruginosa (30%) and Escherichia coli (33%), and highest among Acinetobacter baumannii (97%); the latter included 8 (22%) with extensive drug-resistance (XDR), half of which were resistant to all antibiotics tested. MDR bacteraemia was more likely to be healthcare-associated than community-onset (RR 1.67, 95% CI 1.04–2.65). Inpatient mortality was 22%, 35% and 63% for non-MDR, MDR and XDR episodes, respectively (P = 0.004). Competing risks survival analysis revealed increasing mortality linked to longer hospitalisation with increasing AMR levels, as well as differential pathogen-specific effects. A. baumannii bacteraemia was the most fatal (14-day death hazard ratio 3.39, 95% CI 1.74–6.63). Differences in microbiology, AMR profile and associated mortality compared to national and international data emphasise the importance of similar investigations of local epidemiology.