The film begins in present day 2005 New Orleans. An elderly woman, Daisy Fuller is in a hospital as she is being made comfortable during her last hours of life as she is terminally ill. She tells her daughter about a clockmaker who crafted a magnificent clock right after World War I, which when unveiled ran backwards. He announced to everyone that he made it this way so that the soldiers lost during the War, including his son, could come home and live their lives which had been taken from them in battle. Daisy then asks her daughter to read from a diary which belonged to a Benjamin Button.
We learn that a child was born in 1918, the same year the clockmaker created his clock for the train station. The child, though only an infant, appeared as an elderly man and was abandoned by his father on a doorstep after the mother passed away while giving birth to him. The child is found by a woman named Queenie and a Mr. Weathers who work at the nursing home where the infant was abandoned. Queenie chooses to raise the child, and with the years passing, the young man, Benjamin grows. But, even at his youthful age he appears as if he is as old as every person in the nursing home. He struggles with hearing and his eyesight. When Benjamin is 12 he meets a young, 7 year old girl named Daisy and they become very close.
Eventually, Benjamin leaves Queenie and what he has known as home and joins a tugboat as part of the crew as the Captain believes him to be far older than he truthfully is. Benjamin is constantly mistaken as being an older man as his body grows and he seems to become more and more youthful. By the time the Japanese bomb Pearl Harbor, Benjamin is still part of the Captain's crew and volunteers to join the Captain in salvage work for the U.S. Navy. When out on orders the crew encounter a German submarine which surfaces, and the Captain rams the underwater vessel with his tug boat causing both ships to sink. Benjamin survives unlike most of the crew including the Captain.
Benjamin then returns to his home in New Orleans and to his adopted mother, Queenie. He also reunites with Daisy who tries to seduce Benjamin, but he doesn't reciprocate her advance. After this rejection Daisy leaves. Finally, Benjamin learns the identity of his father, Thomas who he meets as he is terminally ill. He learns his Dad has a button factory which he leaves to Benjamin, including his estate.
Two years pass and Benjamin strikes out to New York City where Daisy lives as a dancer in the ballet. But he learns that she has fallen for another man and he is crushed, and can't carry on trying to go after her. It isn't until 7 years later in 1954 that the two meet again after Daisy has been injured after being hit be a car in Paris which ends her dancing career. She demands he not stay around as she is crushed by her leg injury which has stolen her dream. Eventually, though, Daisy returns to New Orleans and she and Benjamin begin a love affair which culminates in them being married and having a daughter.
But, Benjamin fears that his reverse-aging will not allow him to be a good father to his daughter and he decides to leave her and Daisy. He leaves them with a bank book so that they will always be taken care of financially. Ten years later Benjamin arrives back in Daisy's life, but she is remarried and their daughter is much older. Daisy hides Benjamin's true identity from everyone and admits that he made the right choice to leave. They have a final night of romance before Benjamin once again leaves.
Their paths would cross one final time in the 1990s as Daisy is called by a social worker who has found a young Benjamin displaying early signs of dementia, though he looks as young as 12 years old. Daisy's name was in his diary and that is how they contacted her. Daisy cares for Benjamin until his death in 2003. He is 84 years old, but the size of an infant baby. His death comes one year after the clock in the train station, which had been running in reverse since 1918 was replaced. Daisy has told this story to her daughter Caroline in order that she would finally know the true story of her father. Daisy dies just as Hurricane Katrina hits New Orleans, and the film ends with the clockmaker's clock being seen in a storage room as the flood waters begin to surge towards the clock which hasn't stopped ticking backwards through time.
