The Niners, though, have made the Super Bowl just once in that span and begin the 2014 season on Sunday at AT&T Stadium versus the Dallas Cowboys missing two key pieces from that defense.
San Francisco placed All-Pro linebacker NaVarro Bowman on the reserve/physically unable to perform list prior to the season as he recovers from a torn ACL in his left knee suffered during January's championship game versus Seattle. He will have to miss at least the first six games of the season before being eligible to be activated.
Outside linebacker Aldon Smith, meanwhile, was handed a nine-game suspension at the end of August for violating the league's Policy and Program for Substance of Abuse and the league's Personal Conduct Policy. Smith was sentenced to 11 days in jail and three years' probation back in July on weapons and DUI charges.
That puts the Niners a bit behind the eight-ball to begin the season, but the club is counting on depth and newly-extended quarterback Colin Kaepernick to make up the difference.
"Again, it's a new year, this is a rebirth," noted Niners head coach Jim Harbaugh. "I know I've made that analogy before. You're reborn in football into a new season. One of the things, we're reborn this year into some very high expectations. We welcome that."
While the Niners have been a force under Harbaugh, winning back-to-back NFC West titles before earning a wild card berth last season, the Cowboys have struggled to three straight 8-8 campaigns under coach Jason Garrett and have not made the playoffs since 2009.
The Cowboys had a chance to win the NFC East in 2013, but lost their season finale to Philadelphia at home.
Dallas' defense has also been hit hard prior to the start of the year. Having already lost linebacker DeMarcus Ware and defensive tackle Jason Hatcher to free agency, talented middle linebacker Sean Lee will miss the year because of a torn ACL suffered during team OTAs. Starting cornerback Orlando Scandrick has also been suspended for the first four games of the 2014 NFL season for violation of the performance-enhancing drugs policy.
However, quarterback Tony Romo seems ready to go following December surgery on a herniated disc. He has been taking it slow while recovering, but is expected to play in Week 1.
"The thing I kept reminding Tony about as we went through this process starting all the way back in the spring is, the goal is to be ready for the 49ers -- Sept. 7 at our stadium against the 49ers," Garrett told Dallas' website.
The Cowboys have won three straight and four of their last five versus the Niners to even the all-time series at 16-16-1. This marks the first time the clubs are meeting on opening weekend.
WHAT TO WATCH FOR
All eyes will be on how San Francisco's defense makes out with Smith and Bowman.
San Francisco managed without Smith for five games last season when he voluntarily left the team for five games to seek help for a substance abuse policy.
But now the challenge is greater without Bowman making plays out the middle spot.
"At times, it will be challenging," defensive coordinator Vic Fangio said of missing both Smith and Bowman. "You know, any time you lose two great players, somebody's got to go in there and do the job. We don't expect those guys to be as good as those two guys are, they're at the top of their profession. But we'll find a way."
With Bowman out, fellow All-Pro linebacker Patrick Willis, himself a tackle machine, is expected to shift into Bowman's strong-side spot with former undrafted free agent Michael Wilhoite joining the starting lineup. He made two starts last season when Willis was injured.
Veteran Dan Skuta and second-year pro Corey Lemonier will likely platoon in filling in for Smith like they did last season when he left the team.
On offense, Kaepernick enters his second full seasons as a starter having signed a six-year extension worth a reported $126 million.
San Francisco added to its receiver depth by trading for former Buffalo Bill Stevie Johnson and signing Brandon Lloyd to mix in with tight end Vernon Davis and wideout Anquan Boldin, but the biggest upgrade could be a healthy Michael Crabtree.
Crabtree tore his left Achilles during OTAs in May of 2013 and did not return until Week 13.
"I mean, even the end of last season he wasn't 100 percent and he was making plays for us," Kaepernick said of the wideout. "I'm excited to see what he's going to do now that he's 100 percent."
Also back in the mix is guard Alex Boone, who finally reported to the team this week after staging a prolonged holdout over dissatisfaction over his contract.
For the Cowboys, they'll hope that Rome and star wideout Dez Bryant can find some space against the 49ers. Romo threw for nearly 4,000 yards with 31 touchdowns and 10 interceptions in 15 games last year, while Bryant posted his second straight 1,000-yard receiving season while grabbing career highs of 93 passes and 13 touchdowns.
"Truthfully, to be honest, I feel like, man, I'm still rising. I learn new things and things just become easier by the day," Bryant said. "To me, it's almost kind of scary to me just because of the fact of how much I love the game -- not only myself, I want my teammates to be great. The way that I feel, I don't hesitate to share that with my teammates. And I'm going to continue to keep doing that and see where we go from there."
Also set to test the shorthanded Niners defense is running back DeMarco Murray, who ran for 1,121 yards last year and was also very active in the passing game.
With Lee out, the Cowboys are taking a chance on Rolando McClain. He has had his fair share of off-the-field issues and was given a chance to redeem himself by Dallas. The former Alabama star linebacker had his rights acquired in a trade with Baltimore and hasn't played in the NFL since November of 2012.
"I just had a lot of outside distractions, and if you can't be 100 percent at your job, you're not going to be your best at it ... plain and simple," McClain said. "My thing, I had to eliminate those distractions, understand football is my job, my livelihood. When you're away from the game, you realize how much you miss it, so now you take advantage of the opportunity you're given and do the best you can do."
Injuries and suspensions have robbed this game of some star power, but there will still be plenty of action in Big D.
Kaepernick has a number of new options in the passing game and San Francisco always runs the ball well. That shouldn't change against a Dallas club that ranked last in total defense in 2013, yielding 415.3 yards per game.
That could force Dallas to run-and-gun with the Niners, and though Bryant is one of the best in the game, it will rob Dallas the chance of easing Romo back into game action and even a defense minus Smith and Bowman should force Dallas into enough mistakes to win the ballgame.
Sports Network Predicted Outcome: 49ers 27, Cowboys 20
Notable deaths of 2014 [PHOTOS]
Michael Sam cut from the Dallas Cowboys