Chip Kelly's side are one of just three teams to have enjoyed a perfect start to the new NFL campaign, with the others - the Cincinnati Bengals and Arizona Cardinals - enjoying their bye weeks at the first opportunity.
But Philadelphia should face a stern test versus a Niners outfit that have fallen to defeats in their last two outings.
Jim Harbaugh's men entered the season as one of the favourites having reached at least the NFC Championship Game in each of the last three campaigns.
But an array of injuries and suspensions have depleted San Francisco, who followed up a win over the Dallas Cowboys by losing against the Chicago Bears and the Cardinals.
In stark contrast to the 49ers, Dallas recovered from their opening-game loss with triumphs against the Tennessee Titans and St Louis Rams.
Dallas, too, face a mouth-watering match-up against the New Orleans Saints, who grabbed a first win on Sunday when beating the Minnesota Vikings having surprisingly started 0-2.
An exciting week four line-up also features one of the biggest rivalries as the Green Bay Packers attempt to put an unexpected 1-2 start behind them in Chicago.
The action kicks off with a divisional encounter when the New York Giants head to Washington on Thursday evening.
It remains to be seen whether quarterback Ryan Tannehill will start when the Miami Dolphins head to London's Wembley Stadium to face the Oakland Raiders.
Head coach Joe Philbin was surprisingly noncommittal on Tannehill's starting position this week, although the expectation is that the third-year man will get the nod.
That encounter is one of seven Sunday early games, with others pitting the Buffalo Bills against fellow 2-1 side the Houston Texans, the Tennessee Titans against the Indianapolis Colts, the Carolina Panthers against the Baltimore Ravens and the Tampa Bay Buccaneers against Pittsburgh Steelers.
The Jacksonville Jaguars will attempt to grab their first win of the campaign against the San Diego Chargers and the Atlanta Falcons travel to the Minnesota Vikings. The New York Jets play host to the Detroit Lions.
The round is wrapped up on Monday evening, with the New England Patriots aiming to move to 3-1 when making the tricky trip west to meet the 1-2 Kansas City Chiefs.
The Cleveland Browns, Denver Broncos, St. Louis Rams and Seattle Seahawks join Arizona and the Bengals by having a week off.