Normally, the league announces such violations on Monday. News of Welker's ban didn't come down until late Tuesday, after the league offices had closed and the Broncos had already finished drawing up blueprints for their opener against Indianapolis, undoubtedly with Welker playing a prominent role.
ESPN first reported Welker's suspension, saying the violation had to do with amphetamines.
Welker told the Denver Post in an email that he was ''as shocked as everyone at today's news.'' He noted he's meticulous about what he puts in his body and would ''never knowingly take a substance to gain a competitive advantage in any way.''
The 11th-year pro who's been the NFL's top slot receiver over the last decade added that he never concerned himself with the league's drug rules but now realizes those policies ''are clearly flawed.''
While it takes multiple violations of the league's substance-abuse policies to trigger a suspension, a four-game ban is issued for a single violation of the NFL's ban on performance-enhancing substances.
Welker's suspension will cost him roughly $706,000 in base salary.
''Tonight's news regarding Wes is very disappointing, but we understand the league's authority in this area,'' coach John Fox said in a statement. ''While it's unfortunate to not have him to start the year, I have full confidence in our wide receivers and expect that group to continue playing at a high level.''
Welker played a key role in the two greatest statistical offenses in NFL history: the 2007 New England Patriots and last year's Broncos.
He caught 73 passes for 778 yards and a career-high 10 TDs despite missing the last 3 1/2 games of last season. He returned for the playoffs and had 18 catches for 160 yards and a TD.
Without Welker, Peyton Manning will have to lean more on speedy wide receiver Emmanuel Sanders, who's played in the slot before, or tight end Jacob Tamme, who filled the role at times last year when Welker was out.
Tight end Julius Thomas is also better working the middle of the field. And if Sanders moves inside, that opens up playing time for rookie Cody Latimer or Bubba Caldwell opposite flanker Demaryius Thomas.
''I have no doubt that Wes will remain focused on his preparations for the season and stay in excellent shape during his time away from the team,'' Fox said.
Even before Welker's ban was issued, the Broncos were facing a daunting first month to open the season. Kicker Matt Prater has been suspended for the first four games for an alcohol-related violation of league rules and leading tackler Danny Trevathan is out for the first three games with a broken left leg.
Welker will miss games against Indianapolis, Kansas City, Seattle and Arizona. All four teams won 10 or more games last season.
The Seahawks and Colts both feature physical defensive backs that roughed up the Broncos' receivers at the line of scrimmage in wins over Denver last season.
Adept at getting open in 1-on-1 coverage and finding the holes in zones, Welker hit it off immediately with Manning last year after spending six seasons in New England with Tom Brady.
Welker was excused from practices for two days last month, apparently to meet with league officials about his pending suspension. He then played in a preseason game against Houston on Aug. 23, when he sustained his third concussion since Nov. 17.
Welker returned to practice Monday but declined comment afterward, saying he had to rush to a team function.
His latest head injury came when he tried to duck following a catch over the middle and absorbed a helmet hit by D.J. Swearinger.
Swearinger's hit knocked Welker from the game and drew a 15-yard penalty and the wrath of Manning. The quarterback raced up to say some choice words to the swaggering safety, drawing his first taunting penalty of his career. He was later fined $8,268.
''Obviously, I'm concerned about Wes,'' Manning said after the game. ''I didn't like seeing him come out of the game with a blow to the head. He had one of those last year that kept him out for a while.''
Welker will now be out of action until Oct. 12, when the Broncos visit the Jets.
AP NFL website: www.pro32.ap.org and www.twitter.com/AP-NFL
Follow AP Pro Football Writer Arnie Melendrez Stapleton on Twitter: https://twitter.com/arniestapleton