It was stated in the first film's commentary that there were no plans for a sequel, but due to the first film's impressive box-office performance, earning $347.5 million worldwide, a sequel was given the go-ahead in 2005. It took 38 days of release for the sequel to out-gross the original.

The film premiered in New York City on December 13, 2007, and was first released in Korea and Taiwan on December 19, 2007. It was then released in Australia and the Middle East on December 20, 2007. The film opened in the United States, Canada, Japan, Spain, and Italy on December 21, 2007. It was released in Germany and The Netherlands on January 24, 2008, and in the United Kingdom and Denmark on February 8, 2008.

Plot
In 1865 after the Civil War, Thomas Gates and his son Charles Carroll Gates are approached by John Wilkes Booth and Michael O'Laughlen, both of them Knights of the Golden Circle. They ask Thomas, a skilled puzzle-solver, to decode a playfair cipher written in Booth's diary. O'Laughlen stays with Thomas as Booth leaves to assassinate President Abraham Lincoln. Just as Thomas discovers the message is a map to Cíbola, the fabled City of Gold, pandemonium arises in the streets from the President's assassination. Thomas realizes that Booth and O'Laughlen are still loyal to the South, tears the pages from the diary, and tosses them into a fire before O'Laughlen can shoot him. O'Laughlen only manages to save a partial page from the fireplace before escaping, while Thomas' dying words to Charles are "the debt that all men pay".

The film then shifts to modern day (140 years later), where Benjamin Gates (Nicolas Cage), Thomas's great-great-grandson, is retelling Thomas' story at a Civilian Heroes conference. He and his father Patrick Gates are publicly accosted by Mitch Wilkinson, a black market dealer who has come into possession of the diary page, which appears to link Thomas to Booth and Lincoln's assassination. Ben determines to solve the puzzle on the page to restore Thomas' legacy.

Special Agent Sadusky of the FBI finds it suspicious that a black market dealer like Mitch would suddenly come forward with a rare Civil War artifact. Ben’s technology-savvy friend Riley Poole (Justin Bartha) just had his Ferrari impounded when he was giving out his government conspiracy books then later meets up with Ben.

Ben and Riley discover the cipher on the diary page that says Laboulaye Lady, which points to a hidden inscription on the scale model of the Statue of Liberty on the Île aux Cygnes in Paris, thanks to Thomas' last words. The inscription points to the two Resolute desks, one of which is in the Queen's chambers in Buckingham Palace, the other in the Oval Office of the White House. Ben is unaware that Mitch is following in his footsteps, using a clone of Patrick's cell phone to intercept messages. In London, Ben discovers that Patrick has sent Ben's ex-girlfriend Abigail Chase (Diane Kruger) to help. They are able to sneak into the Queen's quarters and find that the Resolute desk acts as a puzzle box, revealing a hidden compartment with a centuries-old plank of wood with indecipherable hieroglyphics on it. Ben then manages to photograph it (using a traffic camera) before Mitch and his men steal it after a car chase through London. Patrick indicates the plank leads to Cíbola, the City of Gold.

Native American history says that explorers came to the New World to search for Cíbola after its first discovery in 1527, but never could find it. Ben convinces Patrick to help them arrange a meeting with Dr Emily Appleton, Ben's mother and Patrick's ex-wife. Emily is able to translate part of the plank but states that the message is incomplete. Abigail uses her current boyfriend Conner, a member of the White House staff, to allow Ben to sneak into the Oval Office, but Ben finds the Resolute desk compartment empty, save for a symbol (an eagle with a scroll) representing the supposed "Book of Secrets". Riley asserts that the Book is real, having himself just written a book on its existence, and claims that it contains the truth behind many conspiracy theories: such as the missing 18½ minutes of the Watergate tapes, coup d'état of Area 51, the truth about the Apollo program, and the mysterious assassination of President John F. Kennedy. However, traditionally the only person to know the whereabouts of the Book of Secrets is the current President (Bruce Greenwood) himself, since it's for Presidents' eyes only.

Ben and his team manipulate events to assure that the President's birthday celebration occur at Mount Vernon, allowing Ben to sneak in and lure the President alone to a set of disused tunnels. Ben then blocks off the entrance, trapping the President alone with him so that they can talk about the Book of Secrets. Though the President warns Ben that he will be charged with kidnapping the President, he is sympathetic to Ben's cause and provides him with the Book's location at the Library of Congress. Ben, Abigail, and Riley locate the Book as the FBI, including Sadusky, surround the building. In the Book they find that President Calvin Coolidge had found the other half of the plank in 1924 and destroyed it, after taking a photo (which is still in the Book). He also ordered Gutzon Borglum to carve Mount Rushmore into a hill to erase the landmark indicated on the plank, in order to protect Cíbola. As Ben and his team elude the FBI, he sends an image of the plank to Patrick to give to Emily to decode, unaware that Mitch has intercepted this and is waiting for Patrick. Emily is forced to lie to Patrick about the inscription's meaning, but is able to give him a non-verbal cue of this falsehood.

Ben, Patrick, Abigail and Riley arrive at Mount Rushmore, prepared to deal with Mitch, but find that Mitch has brought Emily along, using her as a hostage to ensure Ben follows the final clues on an old letter sent from Queen Victoria to Confederate general Albert Pike that was meant to help a divided America. Ben is able to find the secret entrance, and the group avoids several traps before arriving at the underground site of Cíbola, the City of Gold. Mitch apologizes to Ben for damaging his family name. As they explore, they accidentally cause the cave to flood with water from a lake above. The only means of escape is through a drainage door that must be held open on one side to allow the rest to escape and closed afterwards, trapping the one controlling the door. Mitch initially forces Ben to sacrifice himself, but after a surge of water, Mitch finds himself holding the door open. He requests that part of this discovery be in his name. Ben and the others escape safely.

Ben and his friends are met by Sadusky and taken to a nearby military base. Ben is cleared of kidnapping by the President himself, who claims that Ben rescued him after the tunnel closed accidentally. Thomas Gates' name is cleared and he is called a hero of the Civil War. Sometime later, Cíbola's discovery is announced, with Ben, his team, and Mitch given credit for its discovery. Patrick and Emily, happily working together, eagerly take to the task of analyzing Cíbola once it is drained of water. Ben and Abigail rekindle their broken relationship during the celebration at Mount Rushmore. Riley arrives home to find that the President has given his Ferrari back "tax free". It is also seen that at the end, the President requests for Ben's opinion on Page 47, to which Ben replies is a life-altering answer. When Riley asks them whether it is the Book of Secrets they are talking about, the President denies by asking him which book he is referring to with an enigmatic look. The only mystery remaining is what the President asked Ben to decipher on Page 47 of the Book.

Reception
Critical response
National Treasure: Book of Secrets has received mixed to negative reviews from critics. Rotten Tomatoes reported that 34% of critics gave the film positive reviews based on 123 reviews. Metacritic reported the film had an average score of 48 out of 100, based on 26 reviews, while British film critics disputed the implication of British support for the Confederate side in the American Civil War. The film earned two Razzie Award nominations including Worst Actor for Nicolas Cage (also for Ghost Rider and Next) and Worst Supporting Actor for Jon Voight (also for Bratz: The Movie, September Dawn and Transformers).

Box office
The film opened at number one with $16,739,339 on its first day, and $44,783,772 its first weekend, the third largest Christmas opening. It reached the $100 million mark in eight days, half the time it took the first film. It stayed at number one for 17 days before dropping to number two, and grossed $457,364,600 worldwide, making it the ninth highest grossing film of 2007.