Odom's suspension takes effect immediately.
He faced a suspension earlier this season but appealed, which slowed the process. Now Odom will begin sitting out games starting Oct. 24 against the Atlanta Falcons, once the Bengals (2-3) complete their bye week.
While not naming the specific drug or substance at issue, Odom's lawyer said the player had mistakenly ingested his wife's weight-loss medicine.
Attorney David Cornwell said the suspension illustrates why the NFL's disciplinary programs need an overhaul.
"Antwan did not take a steroid or any other performance enhancing substance," Cornwell said in a statement. "While driving after midnight from Alabama to Cincinnati to report to training camp, Antwan's wife mistakenly opened her prescription pill bottle instead of Antwan's and gave him one of her prescription weight-loss pills instead of Antwan's medicine. Naturally, Antwan's preseason urine test was positive for his wife's medicine."
Odom has been battling injuries this season -- he left last Sunday's loss to Tampa Bay with an undisclosed injury -- and has just four tackles and no sacks.
In October 2009, when he needed surgery to repair a torn Achilles tendon, Odom was the Bengals' top pass rusher and was tied for the league lead with eight sacks.
Per policy, the NFL does not reveal which substance was involved or comment on suspensions stemming from performance-enhancing substances.
Cornwell said the NFL's hearing officer assigned by commissioner Roger Goodell that took up Odom's appeal concluded the evidence showed Odom had inadvertently taken his wife's medicine and called the suspension "unfairly harsh."
But the official, Harold Henderson, "lacked the authority to alter the discipline," Cornwell said.
"The NFL did not dispute the facts in this case and accepted the Cincinnati Bengals' weight records showing that Antwan's target reporting weight was 275 lbs. and that he actually reported at 255 lbs., confirming that Antwan had no reason to take a weight-loss medicine," Cornwell said in the statement. "The steroid program's administrator, Dr. John Lombardo, testified that no competitive advantage was gained by this mistake and that no physical difference would be apparent to Antwan from taking his wife's medicine as opposed to his own."
Informaton from ESPN.com's James Walker was used in this report.