Coach Ken Whisenhunt announced his decision to go with Skelton over Kevin Kolb on Friday.
Skelton and Kolb had waged a protracted competition for the job over offseason workouts and through the preseason.
"I'm not going to get into the specifics of everything that was involved but it's fair to say at this point going forward we feel like the quarterback that gives us the best chance to win right now is John Skelton," Whisenhunt said.
Skelton is in his third season with Arizona after being drafted in the fifth round out of Fordham. Skelton, who grew up in El Paso, Texas, stands 6-foot-6 and has a cannon arm but sometimes struggles with accuracy.
"This is truly the first offseason he's had to work," Whisenhunt said, "and I've seen progress from him. He's a guy that's believed in himself. At times, he's shown he could make plays. At times, he's looked like a young quarterback."
The Cardinals made the decision despite their significant investment in Kolb, who was acquired just before last season in a trade that sent cornerback Dominique Rodgers-Cromartie and a second-round draft pick to Philadelphia.
The Cardinals then signed Kolb to a five-year, $63.5 million contract extension with $21 million guaranteed.
Kolb was handed the starter's job when he arrived in the desert, but after a season-opening win over Carolina, the Cardinals went into a six-game skid. When he went down with a turf toe injury, Skelton took over, as he did when Kolb was sidelined with what turned out to be a season-ending concussion.
Skelton was 5-2 as a starter last season (6-2 if the San Francisco game, when he came in after Kolb was hurt on the first series, is considered). In his last 10 games, nine as a starter, he has directed six game-winning drives in the fourth quarter. But his overall statistics have been mediocre. Last season, he completed 54.9 percent of his passes for 1,913 yards and 11 touchdowns with 14 interceptions.
"It's kind of a weight off my shoulders, I think," Skelton said. "You know, the speculation and waiting is over. But at the same time I think there's another weight placed on. Now you have to move forward as a starter and think of it that way."
He said he always thought Whisenhunt would give him a fair shot at the job, despite the franchise's significant investment in Kolb.
"As soon as the season ended last year and coach Whisenhunt took me in his office and said, 'We're going to give you a chance to compete for the starting job,' I knew he was going to be a man of his word," Skelton said.
But if Skelton has a sufficiently bad stretch, Whisenhunt would be ready to switch quarterbacks.
"I don't think it's different than any other position," the coach said. "This business is a tough business and it's a production-oriented business. If you're not getting the job done, then you're going to be replaced. Our expectation and why we made this decision is that he's going to get the job done."
Kolb saw more game action that Skelton in the preseason, although each quarterback got two starts. Kolb completed 22 of 37 passes (59.5 percent) for one touchdown with three interceptions. Skelton was for 14 for 25 (56 percent) for 131 yards, also with a TD pass and three picks.
Whisenhunt insisted he was "not disappointed" that the addition of Kolb hasn't worked out better.
"There's no guarantee going forward that Kevin won't be playing for us or won't be the starter for us at some point," Whisenhunt said. "We're talking about right now and the process of evaluating this position and that's where we are right now."
Skelton talked about his long journey from third-string quarterback as a rookie to being designated the season-opening starter.
"It's kind of vindication for all the hard work that I've put in," he said. "It seems like I've come a long way since being drafted in the fifth round and starting as a third stringer my rookie year, eventually playing, and then playing last year. But you know it's just hard work paying off and having the opportunity and being ready for that opportunity.
"Now I see myself as the starter. I'm just going to keep moving forward and not look back."
The news wasn't all good for Skelton, though.
His brother, tight end Steve Skelton, was cut by the Cardinals on Friday, the quarterback said on Twitter.
"Rough day seeing friends, including @steveskelton44 let go," John Skelton tweeted. "At the same time excited to get the starting job. Lets get it #birdgang."
Information from The Associated Press was used in this report.