With the increase in keeping exotic companion mammals as pets, concerns about antimicrobial resistance (AMR) and its impact on animal and human health are growing. Guinea pigs, a popular pet in Hong Kong and globally, have limited studies regarding antimicrobial culture and sensitivity results. We reviewed bacteriologic and antimicrobial sensitivity results from clinically ill pet guinea pigs from 2019 to 2023 using data from the City University Veterinary Diagnostic Laboratory. Of the 234 clinical samples from 22 veterinary clinics in Hong Kong, 134 (57.3%) showed positive bacterial growth, of which 23 (17.2%) showed mixed bacterial growth. In total, 156 bacterial isolates were identified. Gram-positive bacteria (n = 104, 66.7%) were most commonly recovered, representing 25 bacterial species, most commonly Streptococcus spp., Staphylococcus spp., and Corynebacterium spp. The majority of positive samples were from the integument (43.6%) and urinary tract (33.8%). A total of 85.9% of all isolates were resistant to at least one antimicrobial agent, with over 40% of isolates exhibiting resistance to three or more antimicrobial agents, and 27.6% were multidrug resistant (resistant to at least one agent in three or more antimicrobial classes). High resistance rates were observed for penicillin (45.6%), gentamicin (43.7%), doxycycline (42.1%), and azithromycin (36.3%). In contrast, isolates were highly susceptible to ceftazidime (84.1%), chloramphenicol (82.6%), ciprofloxacin (72.7%), and marbofloxacin (72.2%). These findings highlight the high frequency of AMR in this population of clinically ill pet guinea pigs in Hong Kong and the need for informed and judicious antimicrobial use.