The league has agreed to compensate sufferers, pay for medical exams and underwrite research - subject to approval by a federal judge - just days before the start of the 2013 season.
More than 4,500 former athletes - out of a total of 18,000 retired players - have sued the NFL since 2011, claiming the long-term dangers of concussion have been concealed and that injured players have returned to action too quickly.
NFL executive vice president said: "This agreement lets us help those who need it most and continue our work to make the game safer for current and future players.
"We thought it was critical to get more help to players and families who deserve it rather than spend many years and millions of dollars on litigation."
Of the settlement, USD 675million will be set aside for compensation, with USD 75million earmarked for medical exams and USD 10million for research.
It means former NFL players are eligible to seek care, screening or compensation. The amounts they receive will be based on their age, condition and years of play, with the highest pay-outs of USD 5million going to those with Alzheimer's.
There is no requirement for former players to prove their condition stems from an on-field injury.
Former New England Patriots running back Kevin Turner, 44, has motor neurone disease and will be eligible for compensation under the agreement.
He told www.nbcnews.com: "[This] will lift a huge burden off the men who are suffering right now.
"It's easy to forget just how many men have played in the NFL throughout the years. In the future they may wind up unfortunately like me, and they know that is a real probability."
The league insisted safety has always been a top priority, and in settling the thousands of cases it admitted no wrongdoing.