Background The incidence of microorganisms with extended-spectrum beta-lactamase (ESBL) is on the rise, posing a significant public health concern. The current application of machine learning (ML) focuses on predicting bacterial resistance to optimize antibiotic therapy. This study employs ML to forecast the occurrence of bacteria that generate ESBL and demonstrate resistance to multiple antibiotics (MDR). Methods Six popular ML algorithms were initially trained on antibiotic resistance test patient reports (n = 489) collected from Al-Hussein/Salt Hospital in Jordan. Trained outcome models predict ESBL and multidrug resistance profiles based on microbiological and patients’ clinical data. The results were utilized to select the optimal ML method to predict ESBL’s most associated features. Results Escherichia coli (E. coli, 82%) was the most commonly identified microbe generating ESBL, displaying multidrug resistance. Urinary tract infections (UTIs) constituted the most frequently observed clinical diagnosis (68.7%). Classification and Regression Trees (CART) and Random Forest (RF) classifiers emerged as the most effective algorithms. The relevant features associated with the emergence of ESBL include age and different classes of antibiotics, including cefuroxime, ceftazidime, cefepime, trimethoprim/ sulfamethoxazole, ciprofloxacin, and gentamicin. Fosfomycin nitrofurantoin, piperacillin/tazobactam, along with amikacin, meropenem, and imipenem, had a pronounced inverse relationship with the ESBL class.