The court declined to hear a challenge to a lower court ruling made in Philadelphia in April.
The court declined to hear a challenge to a lower court ruling made in Philadelphia in April, meaning the deal will now go ahead as planned.
A group of players had objected to the terms of the settlement, arguing it does not provide adequate compensation for victims of chronic traumatic encephalopathy (CTE), a disease which has been found in several deceased players' brains but is impossible to diagnose in living people.
The settlement covers more than 20,000 retired players based on brain injuries linked to concussions during their careers.
The agreement will remain in effect for the next 65 years.
Lawyers for players who accepted the deal welcomed Monday's ruling.
"This decision means that, finally, retired NFL players will receive much-needed care and support for the serious neurocognitive injuries they are facing," said attorney Christopher Seeger.
"These courageous men and their families, who in the face of great adversity took on the NFL, have made history. Despite the difficult health situations retired players face today, and that many more will unfortunately face in the future, they can take comfort in the fact that this settlement's significant and immediate benefits will finally become available to them and last for decades to come."
The NFL also applauded the court decision.
"We look forward to working with class counsel ... to implement the settlement and provide the important benefits that our retired players and their families have been waiting to receive," the NFL said.
Under the terms of the settlement, the NFL admitted no fault even though a league official earlier this year acknowledged for the first time a clear link between football and CTE.
It is estimated that some 6,000 former players, or roughly three in 10, could develop Alzheimer's disease or dementia.
According to Sports Illustrated, average payments to players will be around $190,000 depending on the recipient's age and experience.
Players diagnosed with Amyotrophic Lateral Sclerosis or Lou Gehrig's Disease can receive up to $5 million in compensation.
Family members of players diagnosed with CTE can receive up to $4million. Players suffering from Parkinson's and Alzheimer's are eligible to receive up to $3.5 million.