Smith started the Seahawks' 27-26 preseason loss to the Dallas Cowboys on Friday, with Lock subsequently coming in to throw one touchdown pass and three interceptions.
Former New York Jets passer Smith, who moved to Seattle in 2019 after also featuring for the New York Giants and Los Angeles Chargers, looked likely to get the nod after a bout of COVID-19 forced Lock to sit out their second outing of preseason, a 27-11 defeat to the Chicago Bears.
Head coach Pete Carroll confirmed his decision after the loss to Dallas, declaring: "Geno's going to start.
"He's going to start the opener, and he's earned it, he's won the job. With the time frames that got messed up for Drew, he just ran out of time."
Smith, 31, has started all three of Seattle's preseason outings, and said: "Obviously I'm thankful for the opportunity and grateful, but I have a lot of work ahead of me, that was my mindset from the start.
"I'm just getting ready to get out there and win games, and this is just step one in that process. None of this will matter if we don't get out and win the games we're supposed to win."
The Seahawks' season-opening clash with Denver will see them face their former star quarterback Russell Wilson, whose trade took Lock to Seattle earlier this year.