Newton will lead a Carolina Panthers team making their first playoff appearance in five seasons while Kaepernick will call the shots for the visiting San Francisco 49ers, who won the NFC last season before losing to Baltimore in the Super Bowl.
It is a match that has all the makings of a classic as both teams are overflowing with potent offenses and backed by water-tight defenses.
But it is the battle between the two gifted quarterbacks that has captured the most attention in the buildup and looms as the decisive factor in the outcome.
Both men are among the most productive rushing quarterbacks in the game and, if their most recent clash is any guide, the yards gained with their legs could prove more important than the yards gained from their throws.
The teams met once in the regular season, with the Panthers winning 10-9 at San Francisco's Candlestick Park last November. Kaepernick, 26, threw for a season-low 91 yards while Newton, 24, threw for 169 yards in a game dominated by swarming defense.
The 49ers are the slight favorites, although they are on the road for the second consecutive playoff game after edging the Green Bay Packers last weekend.
They have won their last seven games in a row dating back to the regular season, the longest active streak in the NFL, and are brimming with confidence with the experience of playing in last year's Super Bowl still fresh.
"It's not our first time coming off of a big win and getting ready for an even bigger game the next week," San Francisco head coach Jim Harbaugh told reporters.
"This is as much fun as you can possibly have in football and as much fun as you can have in life."
For Newton, Sunday marks his first appearance in the NFL playoffs after the Panthers got a first-round bye but the third-year quarterback is anything but overawed by the occasion.
Success has always come naturally to Newton. He won a college national championship, a Heisman Trophy as the most outstanding college player and was the number one overall pick in the 2011 NFL Draft.
"I feel as if I haven't achieved anything worth mentioning - yet," said Newton, who was the NFL's top rookie for the 2011 season.
"Everyone talks about the great season that myself and others have had, but we all come to each other and say, 'There's nothing worth mentioning unless we have something that we can all share with each other for years and years to come."
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