Antimicrobial resistance has emerged as a critical global concern. Escherichia coli, a prominent Gram-negative bacterium, present significant challenges in infection management due to its adaptive resistance mechanisms. Found naturally in the gastrointestinal tracts of humans and animals, E. coli strains are increasingly resistant to antibiotics worldwide, necessitating urgent intervention strategies. This study aimed to assess the global prevalence and risk variables linked to multidrug-resistant E. coli in human and animal samples via systematic review and meta-analysis. We searched databases like Google Scholar, Scopus and Medline (PubMed) for relevant publications from January 2015 to April 2023. These studies reported on multidrug-resistant E. coli prevalence and associated risk factors. Articles were selected based on predefined criteria. Results were presented with 95% confidence intervals in forest plots, tables, and figures. Heterogeneity was assessed using the inconsistency index (I2). Random-effects model Comprehensive meta-analysis software calculated pooled prevalence and risk factor estimates. The combined prevalence of multidrug-resistant E. coli was estimated at 36.5% (95% CI: 24.6–50.3), showing significant heterogeneity (I2 = 99.13%). Risk variables like length of hospital stay and past history of antibiotic usage have been linked to increased multidrug resistance in E. coli, according to a pooled study of 23 researches that satisfied the meta-analysis eligibility criteria. The pooled odds ratio for risk factors was 1.266 (95% CI: 0.804–1.992), with notable heterogeneity (I2 = 85.92%). Additionally, the odds ratio for prior antibiotic usage was 1.326 (95% CI: 0.837–2.102), and for length of hospital stay, it was 1.162 (95% CI: 0.340–3.973). This study and meta-analysis highlight global concerns regarding antibiotic resistance, particularly the increasing prevalence of multidrug-resistant E. coli. Key-independent risk factors identified include the duration of hospital stays and prior antibiotic use. Effective management and prevention strategies for drug resistance in E. coli and other bacteria should depend on identifying and addressing these risk factors.