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Capybara (Hydrochoerus hydrochaeris) is the main host of tick-borne pathogens causing Brazilian spotted fever; therefore, controlling its population is essential, and this may require chemical restraint. We assessed the impact of chemical restraint protocols on the partial pressure of arterial oxygen (PaO2) and other blood variables in 36 capybaras and the effect of different flows of nasal oxygen (O2) supplementation. The capybaras were hand-injected with dexmedetomidine (5 μg/kg) and midazolam (0.1 mg/kg) and butorphanol (0.2 mg/kg) (DMB, n = 18) or methadone (0.1 mg/kg) (DMM, n = 18). One-third of the animals were maintained in ambient air throughout the procedure, and one-third were administered intranasal 2 L/min O2 after 30 min whereas the other third were administered 5 L/min O2. Arterial blood gases, acid-base status, and electrolytes were assessed 30 and 60 min after drug injection. The DMB and DMM groups did not vary based on any of the evaluated variables. All animals developed hypoxaemia (PaO2 44 [30; 73] mmHg, SaO2 81 [62; 93] %) 30 min before O2 supplementation. Intranasal O2 at 2 L/min improved PaO2 (63 [49; 97] mmHg and SaO2 [92 [85; 98] %), but 9 of 12 capybaras remained hypoxaemic. A higher O2 flow of 5 L/min was efficient in treating hypoxaemia (PaO2 188 [146; 414] mmHg, SaO2 100 [99; 100] %) in all the 12 animals that received it. Both drug protocols induced hypoxaemia, which could be treated with intranasal oxygen supplementation.