Talks between the NFL and the National Football League Players Association (NFLPA) have been ongoing in recent weeks to amend the policy, with a number of issues under the microscope.
A joint statement read: "The NFL and NFL Players Association have reached agreement on wide-ranging improvements to their policy on performance-enhancing substances.
"The NFL and NFLPA are nearing an agreement on changes to the substance-abuse policy that is expected to be announced when it is completed."
Chief among the issues was what some believed to be overly harsh punishments for taking banned stimulants in the off-season.
That is one of several concerns that have been resolved, with players now set to be put in substance-abuse schemes rather than face suspensions - although those who test positive during the campaign will continue to serve four-game bans.
As a result, the previously suspended trio of the Denver Broncos' Wes Welker, the Dallas Cowboys' Orlando Scandrick and the St. Louis Rams' Stedman Bailey will be eligible to return to the field from this weekend.
The new deal is also groundbreaking in its allowance of testing for human growth hormone (HGH).
While some punishments have been scaled back, there will be harsh reprimands in place for performance-enhancing drugs (PEDs).
First-time offenders will serve a suspension without pay of up to six games depending on the nature of the violation; use of a diuretic or masking agent brings a two-game ban, use of a steroid, stimulate, HGH or other banned substance will bring a four-game ban and evidence of an attempt to manipulate the test in a six-game ban.
A second violation of the penalty will result in a 10-game suspension without pay and a third would banish the offender for at least two years.
Appeals will be heard by third-party arbitrators jointly selected by the NFL and NFLPA and will be processed "expeditiously under improved rules and procedures".