After reaching orbit, Sputnik 2's nose cone was jettisoned successfully, however the "Block A" core did not separate as planned, stopping the thermal control system from operating correctly. Some of the thermal insulation tore loose, raising the cabin temperature to 40 °C. After three hours of weightlessness, Laika's pulse rate had settled back to 102 beats/min,[19] three times longer than it had taken during earlier ground tests, an indication of the stress she was under. The early telemetry indicated that Laika was agitated but eating her food. After approximately five to seven hours into the flight, no further signs of life were received from the spacecraft.

The Russian scientists had planned to euthanize Laika with a poisoned serving of food. For many years, the Soviet Union gave conflicting statements that she had died either from oxygen starvation when the batteries failed, or that she had been euthanized. Many rumors circulated about the exact manner of her passing. In 1999, several Russian sources reported that Laika had died when the cabin overheated on the fourth day. On October 2002, Dr. Dimitri Malashenkov, one of the scientists behind the Sputnik 2 mission, revealed that Laika had died five to seven hours after launch from overheating and stress. Over 5 months later, after 2,570 orbits, Sputnik 2 disintegrated—along with Laika's remains—during re-entry on April 14, 1958.
Sputnik 2 was not designed to be retrievable, and Laika had always been intended to die.