•CRE reports has been increasing steadily over the past six years despite aggressive infection-control interventions.•Carbapenemase-producing Enterobacterales with rare carbapenemase genes have emerged and increased over time.•The incidence rate of CRE among patients with indwelling medical devices was lower than those without indwelling medical devices,suggesting a rise of cases in patients with no invasive medical devices who are not a direct target of the device-related infection prevention. Carbapenem-resistant Enterobacterales (CRE) remain an urgent public health priority in the United States. CRE poses a major threat to patients in healthcare and a potential risk to the community. This study examined the epidemiological trends, clinical, and microbiological data of CRE in the Greater Houston region of Texas. A multi-institutional retrospective observational study was conducted using surveillance data collected from 2015 to 2020. Predictors of incidence rates of CRE were determined by a negative binomial regression fit using a generalized estimation equation. Over a 6-year period, 4236 CRE cases were reported, of which Klebsiella pneumoniae accounted for 84.8%. The results show a steady increase in CRE cases, with a sharp rise since 2018. The majority of carbapenemase-producing Enterobacterales were Klebsiella pneumoniae carbapenemase (KPC)-producing (77.2%), followed by other rare carbapenemases, which includes OXA-48, NDM, IMP, VIM, coproduction of KPC with OXA-48, KPC with NDM, and NDM with OXA-48. Acute care hospitals (ACH) accounted for 68.5% of the source of CRE cases. The incidence rate of CRE cases reported from ACH and long-term acute care (LTAC) facilities was 1.16 times that of long-term care facilities (adjusted rate ratio ARR = 1.16, 95% confidence interval CI:1.04–1.30). The incidence rate of CRE among patients with indwelling devices was 15% (ARR = 0.85, 95% CI: 0.79–0.92) lower than that of patients without indwelling devices. The rise in the rate of CRE cases despite aggressive infection prevention and control strategies in the region is alarming. Evaluating and improving the current infection control strategies may be warranted.