Exposure to hydrogen sulfide (H2S) can cause neurotoxicity and cardiopulmonary arrest. Resuscitating victims of sulfide intoxication is extremely difficult, and survivors often exhibit persistent neurological deficits. However, no specific antidote is available for sulfide intoxication. The objective of this study was to examine whether administration of a sulfonyl azide-based sulfide-specific scavenger, SS20, would rescue mice in models of H2S intoxication: ongoing exposure and post-cardiopulmonary arrest. In the ongoing exposure model, SS20 (1,250 µmol/kg) or vehicle was administered to awake CD-1 mice intraperitoneally at 10 minutes after breathing 790 ppm of H2S followed by another 30 minutes of H2S inhalation. Effects of SS20 on survival was assessed. In the post-cardiopulmonary arrest model, cardiopulmonary arrest was induced by an intraperitoneal administration of sodium sulfide nonahydrate (125 mg/kg) in anesthetized mice. After 1 minute of cardiopulmonary arrest, mice were resuscitated with intravenous administration of SS20 (250 µmol/kg) or vehicle. Effects of SS20 on survival, neurological outcomes, and plasma H2S levels were evaluated. Administration of SS20 during ongoing H2S inhalation improved 24-hour survival (6/6 [100%] in SS20 versus 1/6 [17%] in vehicle; P = 0.0043). Post-arrest administration of SS20 improved 7-day survival (4/10 [40%] in SS20 versus 0/10 [0%] in vehicle; P = 0.0038) and neurological outcomes after resuscitation. SS20 decreased plasma H2S levels to pre-arrest baseline immediately after reperfusion and shortened the time to return of spontaneous circulation and respiration. The current results suggest that SS20 is an effective antidote against lethal H2S intoxication, even when administered after cardiopulmonary arrest.