Anesthetizing guinea pigs is difficult with varying outcomes. The primary purpose of the study reported here was to evaluate six injectable anesthetic regimens for use in guinea pigs and assess the depth of anesthesia and, thus, their effectiveness in terms of their use for major surgical procedures. Other variables that were measured and evaluated included time from injection until onset of anesthesia, duration of anesthesia, depth of anesthesia, and vital signs (i. e., respiratory rate, heart rate, and body temperature). Female Dunkin Hartley guinea pigs that were 9 to 12 weeks old were randomly assigned to receive one of the following anesthetic regimens: ketamine/xylazine (KX), ketamine/detomidine (KD), ketamine/medetomidine (KM), 4) tiletaminezolazepam/ xylazine (TX), tiletamine-zolazepam/detomidine (TD), or tiletamine-zolazepam/medetomidine (TM). All anesthetics were administered intramuscularly. Anesthesia was assessed by attempting to perform an ovariohysterectomy. Surgery could not be performed on any guinea pigs in the groups given ketamine or TD. There was a high rate of adverse effects in guinea pigs receiving detomidine. Four of six guinea pigs in the TD group died during or after the anesthetic episode. Fourteen of 30 (46.7%) guinea pigs given TX underwent successful surgery, and 23 of 29 (79.3%) given TM underwent successful surgery. A combination of tiletamine-zolazepam and xylazine or medetomidine was effective for inducing anesthesia and providing sufficient analgesia to perform a major surgical procedure on guinea pigs. However, TM was the most reliable regimen.