Simple SummaryAntimicrobial resistance in exotic pets has not been widely studied. The close contact of this type of animal with the human population increases the risk of untreatable bacterial infections, which represent a veterinary and human public health challenge. We analyze the database of microbiological diagnoses and the bacterial susceptibility to antimicrobials in exotic pets from the Iberian Peninsula. We found that the most prevalent bacteria in birds and mammals were Staphylococcus spp., while in reptiles, they were the Pseudomonas spp. In addition, Pseudomonas showed the highest levels of resistance among the three animal groups, and on the other hand, the multidrug resistance level was significant in Enterobacterales. Most of the bacteria we found have zoonotic importance. The prevalent bacteria are resistant to antimicrobials that have been described as critical for human use, implying that the threat of antimicrobial resistance extends not only to domestic and companion animals but also to humans due to the potential transmission of resistant genes. Once seen from the lens of the One-Health paradigm, these findings are concerning, as they highlight the risk of spreading antibiotic-resistant genes between different individuals and their environments. In order to prevent antibiotic resistance, we encourage the development of joint work between animal and human health specialists.Literature related to antimicrobial resistant (AMR) bacteria in exotic pets is minimal, being essential to report objective data on this topic, which represents a therapeutic challenge for veterinary medicine and public health. Between 2016 and 2020, laboratory records of 3156 exotic pet specimens’ microbiological diagnoses and antibiotic susceptibility testing (AST) results were examined. The samples were classified into three animal classes: birds (n = 412), mammalia (n = 2399), and reptilian (n = 345). The most prevalent bacteria in birds and mammals were Staphylococcus spp. (15% and 16%), while in reptiles they were Pseudomonas spp. (23%). Pseudomonas was the genus with the highest levels of AMR in all animal groups, followed by Enterococcus spp. By contrast, Gram-positive cocci and Pasteurella spp. were the most sensitive bacteria. Moreover, in reptiles, Stenotrophomonas spp., Morganella spp., and Acinetobacter spp. presented high levels of AMR. Multidrug-resistant (MDR) bacteria were isolates from reptiles (21%), birds (17%), and mammals (15%). The Enterobacterales had the highest MDR levels: S. marcescens (94.4%), C. freundii (50%), M. morganii (47.4%), K. pneumoniae (46.6%), E. cloacae (44%), and E. coli (38.3%). The prevalence of MDR P. aeruginosa strains was 8%, detecting one isolate with an XDR profile. Regarding antimicrobial use, many antibiotics described as critically important for human use had significant AMR prevalence in bacteria isolated from exotic pets. Under the One-Health approach, these results are alarming and of public health concern since potential transmission of AMR bacteria and genes can occur from exotic pets to their owners in both senses. For this reason, the collaboration between veterinarians and public health professionals is crucial.