This study aimed to investigate the use of electroencephalography (EEG) for detecting brain activity changes perioperatively in anesthetized horses subjected to surgery. Twelve adult horses undergoing various surgeries were evaluated after premedication with xylazine and butorphanol, induction with ketamine, midazolam, and guaifenesin, and maintenance with isoflurane. The frontal EEG electrodes were placed after the horse was intubated and mechanically ventilated. The EEG data were collected continuously from Stage (S)1—transition from induction to isoflurane maintenance, S2—during surgery, S3—early recovery before xylazine sedation (0.2 mg kg IV), and S4—recovery after xylazine sedation. The Patient State Index (PSI), (Burst) Suppression Ratio (SR), and 95% Spectral Edge Frequency (SEF95) were compared across the stages. The PSI was lowest in S2 (20.8 ± 2.6) and increased to 30.0 ± 27.7 (p = 0.005) in S3. The SR increased from S1 (5.5 ± 10.7%) to S3 (32.7 ± 33.8%, p = 0.0001). The spectral power analysis showed that S3 had a significantly higher content of delta wave activity (0.1–4 Hz) in the EEG and lower relative power in the 3 Hz to 15 Hz range when compared to S1 and S2. A similar result was observed in S4, but the lower power was in a narrower range, from 3 Hz to 7 Hz, which indicate profound central nervous system depression potentiated by xylazine, despite the cessation of isoflurane anesthesia. We concluded that the use of EEG provides clinically relevant information about perioperative brain state changes of the isoflurane-anesthetized horse.