The administration of parenteral penicillin G benzathine/procaine, as well as ceftiofur CFA in guinea pigs and chinchillas, is considered controversial and often recommended against, despite these drugs being routinely administered in rabbits. To date, no prospective or retrospective studies evaluating the use of these drugs in chinchillas and guinea pigs have been reported, making evidence-based recommendations challenging. Therefore, the objective of this retrospective study was to evaluate the use of penicillin G and ceftiofur CFA in pet guinea pigs and pet chinchillas treated at the University of Wisconsin-Madison between 2001-2023. The medical records were evaluated for prescriptions of the two drugs in these two species and information on indications for treatment, doses, outcome, and adverse effects were recorded. 16 guinea pigs and 43 chinchilla patients were treated with penicillin G benzathine/procaine. Ceftiofur CFA was administered to 45 guinea pigs and 26 chinchillas. The most common treatment indications were odontogenic infections such as periodontal disease or periapical abscesses. The median dose prescribed for penicillin G benzathine/procaine was 50000 U/kg and 40 mg/kg SC for ceftiofur CFA. In chinchillas, no adverse effects for either drug were recorded. In guinea pigs, no adverse effects were recorded following ceftiofur administration. Following penicillin administration, one systemically diseased guinea pig with a prolonged medical history was found dead one day after the penicillin injection. In conclusion, prospective studies should be performed to evaluate better the potential adverse effects of either drug in controlled settings.