Thousands of former players have accused league officials of concealing what they knew about the risk of playing after a concussion. The lawsuits allege the league glorified violence as the game became a $9 billion-a-year industry.
Some former players suffer from dementia, depression and other brain diseases, and a few have committed suicide. Others are seeking medical monitoring.
The NFL denies any fraud or negligence, and insists that player safety has always been a priority. The league believes the complaints should go to arbitration under terms of the players' collective bargaining agreement.
U.S. District Judge Anita Brody will hear arguments from Supreme Court litigators Paul Clement for the NFL and David Frederick for the players. Brody's ruling is not expected for several months, and is likely to be appealed by the losing side.
It could be years before the cases are resolved, but some observers believe they could cost the league billions of dollars if the players are successful. Their lawyers hope to use the discovery process to access NFL files, including those on the league's much-criticized Mild Traumatic Brain Injury Committee, which was formed in the 1990s and headed by a rheumatologist, not a neurologist.
Some believe the cases could rival class-action lawsuits against Big Tobacco in terms of the discovery process, although the tobacco litigation involved far more people. About one-third of the league's 12,000 former players have filed suit.
They include two-time Super Bowl quarterback Jim McMahon, who is suffering from early-stage dementia and has said if he had to do it over again, he would play baseball.
Other plaintiffs include the family of Pro Bowler Junior Seau and the widow of lead plaintiff Ray Easterling, both of whom committed suicide last year. Many other players have no symptoms but seek medical monitoring.
The NFL, in motions to dismiss the case, has argued that it has always followed the best available science and made player safety a top priority.
"Medical decisions override everything else," NFL Commissioner Roger Goodell said in a speech last month at the University of North Carolina. He is not expected to attend the hearing.
Clement, a former U.S. solicitor general under President George W. Bush who has fought gay marriage, gun-control measures and President Barack Obama's state health care mandates before the Supreme Court.
Players' lawyer David Frederick, an Obama ally, has taken consumer protection fights over investor fees and prescription drug warnings to the high court.