Cook was re-signed by Oxford last week for £5,000 thanks to a fans' fund
Oxford United won the battle of the Blue Square Premier's unbeaten teams, beating 10-man Luton Town to go five points clear at the top of the table.
Kick-off was delayed as 10,613 fans piled in, and there was early action as James Constable's penalty was saved by Mark Tyler in the third minute.
Within a minute he had opened the scoring from close range and Jamie Cook made it 2-0 with a stunning strike.
Kevin Nicholls then saw red for Luton, who squandered several good chances.
The victory was Oxford's first league win over the Hatters since November 1992.
The game's kick-off was put back 15 minutes (2000 BST) because of crowd congestion, for the biggest attendance since the Blue Square Premier was rebranded in 2007.
The fixture was a top-flight one six times between 1985 and 1988, providing 34 goals between them. And it was Oxford who got off to the brighter start within three minutes of their first meeting since 2001.
Jamie Cook played Constable into the box after two minutes, George Pilkington barged him down, and referee Brendan Malone awarded a penalty.
Constable's goal came just a minute after his missed penalty
Constable stepped up to take the spot-kick only to see it saved well by Mark Tyler. But last season's top scorer took just 60 seconds to atone for the home side.
From Matt Green's break down the right, Constable fired home from six yards for his sixth goal of the season.
Luton were on the ropes and, 10 minutes later, Cook doubled their lead with a stunner on his first ever home game at the Kassam Stadium.
The Witney-born player left Oxford for Boston in 2001 and almost quit football but has worked his way back up, joining the U's last week from Crawley, and taking a pay-cut in the process.
Constable refused to let the ball go out of play from a corner and Cook left a defender for dead with a brilliant turn before rifling home into the top corner from 25 yards.
Luton pressed for a way back into the game, centre-back Alan White firing over from eight yards out.
The Hatters' next chance again fell to the summer signing from Darlington but he headed wide from Tom Craddock's cross.
United suffered a scare when Damian Batt's poor header back almost led Craddock in, but goalkeeper Ryan Clarke saved his full-back's skin.
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