Escherichia coli is an important cause of disease in humans including being the most common cause of bloodstream infections (BSIs). In order to support prioritization of diseases for public health decision-making, a comprehensive understanding of disease burden is required. We evaluated the burden of E. coli infections from different perspectives including incidence rate, mortality rate, case fatality risk, post-infection length of stay (PI-LOS), and the burden attributable to antimicrobial-resistant E. coli infections. Our systematic review and meta-analysis revealed that when considering third-generation cephalosporin (3GC) resistance, quinolone resistance, or multidrug resistance, there was a significant increase in the odds of dying (30-day or all-cause) with resistant E. coli infections compared to susceptible infections. We studied incident E. coli BSIs and 30-day deaths (2014-2018) from national (Finland) and regional (Australia, Sweden, and Canada) surveillance. Mortality data from Australia were not available. Rates were directly age and sex standardized to European Union 28-country 2018 population. Overall and 3GC-resistant standardized rates were 97.4 and 7.1 E. coli BSI/100,000 person-years and increased 12.7% and 34.4% during the study, respectively. The 30-day case fatality risk was 9.6% and standardized 30-day mortality rate was 9.7 deaths/100,000 person-years. Using negative binomial or logistic regression analyses, we examined E. coli BSI rate, 30-day mortality rate, 30-day case fatality risk, 3GC-resistance, and long PI-LOS (>75th percentile). Region, age, and sex were associated with E. coli BSI rate, and age was associated with 30-day mortality rate. Region, year, and an interaction between age and sex were associated with odds of having 3GC-resistant E. coli BSI. Region, location of onset, 3GC resistance, and an interaction between age and sex were associated with 30-day mortality. Detailed case data were available for E. coli BSIs from the western interior, British Columbia (04/2010-12/2018). Location of onset, age, BSI foci, and Charlson comorbidity index (CCI) were associated with 30-day mortality. Extended-spectrum β-lactamase-producing E. coli, location of onset, and CCI were associated with long PI-LOS. These results highlight the increasing E. coli BSI incidence rate, considerable mortality burden and evolving antimicrobial resistance, which have an important impact on human health and healthcare systems, especially in aging populations.