ABSTRACT The ESKAPE ( Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter species) pathogens cause an increasing number of nosocomial infections worldwide since they escape the inhibitory effect of the available antibiotics and the immune response. Here, we report the broad-spectrum and potent antibacterial activity of Kisameet clay, a natural clay mineral from British Columbia, Canada, against a group of multidrug-resistant ESKAPE strains. The results suggest that this natural clay might be developed as a therapeutic option for the treatment of serious infections caused by these important pathogens. IMPORTANCE More than 50 years of misuse and overuse of antibiotics has led to a plague of antibiotic resistance that threatens to reduce the efficacy of antimicrobial agents available for the treatment of infections due to resistant organisms. The main threat is nosocomial infections in which certain pathogens, notably the ESKAPE organisms, are essentially untreatable and contribute to increasing mortality and morbidity in surgical wards. The pipeline of novel antimicrobials in the pharmaceutical industry is essentially empty. Thus, there is a great need to seek for new sources for the treatment of recalcitrant infectious diseases. We describe experiments that demonstrate the efficacy of a “natural” medicine, Kisameet clay, against all of the ESKAPE strains. We suggest that this material is worthy of clinical investigation for the treatment of infections due to multidrug-resistant organisms.