Llambias' resignation comes a day after Joe Kinnear was confirmed as the club's director of football on a three-year deal.
In a short statement on the club's official website, posted 20 minutes before the release of the 2013-14 season fixtures, Llambias said: "I have had an incredible journey during my five years at the club, including some challenging times.
"I will reflect with great fondness on my time in the north east and, in me, Newcastle United have a lifelong supporter.
"I want to thank the staff for their hard work, our fans for their support of the club, and wish them all well for the future."
Llambias, who has worked closely with United owner Mike Ashley since he took over the club in 2007, has polarised opinions of the club's fans during his time at St James' Park.
He has overseen the sales of some of the club's most popular players, such as Andy Carroll and Kevin Nolan, while also being involved in controversial decisions such as the one to appoint Kinnear as manager in 2008 and changing the name of the club's famous ground.
Kinnear's return to the club caused outrage among Newcastle fans, with the 66-year-old giving a radio interview during which he insulted them.
He also pronounced a number of first-team player's names wrong, while also referring to Llambias as Llambeeze.
The ex-Wimbledon manager correctly called Llambias' resignation, before claiming to have replaced him, even though Llambias' job was a different one.
He told talkSPORT on Monday: "I only signed the contract last night. So that was someone speaking to Mike but it's been ongoing for the last three weeks.
"Derek Llambeeze was the director of football. Derek has resigned now."
Kinnear would go on to muddle up a number of players before telling dissenting fans he had "more intelligence than them, that's for sure".
When asked what he would say to the fans, he added: "To all the Newcastle fans who don't do this decision then shall I bring Llambeeze back?"
Llambias arrived at Newcastle in the summer of 2008 and was criticised by the supporters for being part of a so-called 'Cockney Mafia', comprising of himself, Ashley, Tony Jimenez and Dennis Wise, who was installed as a director of football.
Source: Newcastle United Mad