and upheld the sentence of death penalty awarded by the Bombay high court.
The judges also rejected his claim that he had been denied a fair trial.
A trial court convicted Qasab, 24, of murder and other crimes in May 2010. His first appeal was rejected by the Mumbai High Court in February 2011.
The Mumbai attacks claimed 165 lives. Nine gunmen were also killed.
“In view of the nature of the gravity of his crime and the fact that he participated in waging war against the country, we have no option but to uphold his death penalty,” Supreme Court Justices Aftab Alam and CK Prasad ruled on Wednesday morning.
Prosecutor Gopal Subramaniam hailed the verdict as “a complete victory of the due processes of law”.
“It was a case argued in a completely professional and dispassionate manner,” Mr Subramaniam said.
Qasab can now make a plea for clemency to the president.
The trial court in Mumbai had found Qasab guilty on 3 May 2010 of murder, terrorist acts and waging war on India and sentenced him to death.
The 60-hour siege of Mumbai began on 26 November 2008, targeting luxury hotels, the main railway station and a Jewish cultural centre.
Qasab and an accomplice carried out the assault on the station, killing 52 people.
India blamed Pakistan-based militant group Lashkar-e-Taiba for the attacks.
After initial denials, Pakistan acknowledged that the assault had been partially planned on its territory and that Qasab was a Pakistani citizen.