The following week on September 15, San Francisco travels to division-rival Seattle to face the Seahawks in prime time on Sunday night. The overall series is tied at 14 games apiece, but under head coach Jim Harbaugh, the 49ers are 3-1 versus Seattle. The teams split the 2012 series, with each team winning on their home field.

On September 22, San Francisco will host the Indianapolis Colts for the first time since 2005. The 49ers are 18-24 overall against the Colts, including an 11-10 record at home. The Colts defeated the 49ers, 18-14, in the teams' last meeting in Indianapolis, in 2009.

The Niners will have a short week as they will travel to St. Louis for a Thursday night, NFL Network showdown with the Rams on September 26. The overall series is split at 62-62-3, and 31-31-1 on the road. Both contests last season went into overtime, with the Rams winning, 16-13, in St. Louis, and the teams tying, 24-24, in San Francisco.

San Francisco will then return home for two consecutive home games, first facing the Houston Texans on Sunday night October 6, in front of a national audience on NBC. It marks the third prime time appearance through the first five weeks of the regular season for the 49ers. This will be only Houston's second trip ever to Candlestick Park in the regular season, and their first since the 49ers won 20-17 in overtime, in 2005.

The second game of the back-to-back home-stand will be on October 13 vs. the Arizona Cardinals. San Francisco owns a 26-17 overall record against the Cardinals, including a 15-8 mark at home. In the 2012 regular season finale, San Francisco won 27-13, clinching the NFC West Division title for the 19th time in franchise history. The Niners have compiled a 7-1 record versus Arizona over the past eight games.

The 49ers begin their trek East with a stop in Nashville on October 20 to face the Tennessee Titans. San Francisco is 7-5 all-time against the Titans, including a 4-2 mark on the road. The following week, the 49ers will travel across the pond to battle the Jacksonville Jaguars in London, England on Sunday, October 27, at historic Wembley Stadium. The game marks the 11th time the 49ers will play on the international stage, and the third time in the regular season. The team's most recent trip to the UK occurred on October 31, 2010, as the 49ers defeated the Denver Broncos, 24-16, in front of a sellout crowd of 83,941. The 49ers are 1-2 all-time against the Jaguars, having lost both road contests against the team.

Following a bye in Week 9, San Francisco will host the Carolina Panthers for the first time since 2004, on November 10. The Niners hold a 7-10 overall record against Carolina, including 3-5 at home.

On November 17, San Francisco will face the New Orleans Saints in the first of back-to-back road games. The 49ers hold a 47-24-2 all-time series lead against the Saints, including a 24-13 advantage on the road. The Niners defeated the Saints 31-21 last season at the Superdome, marking their second consecutive victory over New Orleans. The following week San Francisco will make its first appearance of the 2013 season on ESPN's Monday Night Football at Washington on November 25. The 49ers hold an 18-10-1 edge in the all-time series against the Redskins, including a 19-11 victory at Washington in 2011.

In Week 13, the 49ers return home to face divisional opponents in consecutive weeks. On December 1, the Niners host the Rams and Seattle will make the trek south to San Francisco the following week on December 8. The 49ers have won the last four home meetings against the Seahawks, including a 13-6 victory in 2012.

The 49ers hit the road for two of their final three regular season games, first traveling to Tampa Bay to face the Buccaneers on December 15. San Francisco leads the all-time series against the Buccaneers 16-5 and has edged out Tampa Bay 4-3 on the road. This marks the 49ers first trip to Tampa Bay since 2004.

San Francisco and Candlestick Park will be featured together in a nationally televised, prime time bout one last time during the regular season, as the 49ers play host to the Atlanta Falcons on ESPN's Monday Night Football on December 23. The matchup will mark the 36th Monday Night Football game that Candlestick Park has hosted since opening in 1971, the most of any stadium in NFL history. San Francisco defeated the Falcons 28-24 in the NFC Championship Game last season, earning the franchise's sixth Super Bowl appearance. The 49ers own the overall series 44-30-1, including a 26-11 mark at home.