Chinchillas are strict herbivorous hindgut-fermenting hystricomorphic rodents that are reportedly susceptible to antibiotic-induced dysbiosis, with potentially fatal outcomes. Therefore, it is recommended not to administer certain oral antibiotics that predominantly target anaerobic bacteria, and aerobic Gram-positive bacteria. However, drugs such as metronidazole or azithromycin are highly effective against anaerobic bacteria without causing clinically apparent dysbiosis of the large intestine in chinchillas. Therefore, the purpose of this prospective study was to evaluate the effects of metronidazole (20 mg/kg PO q24h), azithromycin (30 mg/kg PO q24h), and pradofloxacin (10 mg/kg PO q24h) administered for 5 days on the fecal microbiome evaluated by next-generation DNA sequencing. Treatments were randomized, and two control groups were included (tap water and oral suspension vehicle). Food intake and fecal output were measured daily. Fecal samples were collected on days 0, 7, and 14. Significant shifts in the fecal microbiome were recorded in all treatment groups. Still, only the animals receiving pradofloxacin became clinically affected, with a profound reduction in food intake and fecal output. The results of this study will help us better understand the effects of oral antibiotics in chinchillas and the changes to the large intestinal microbiome following antibiotic administration.