Fullmetal Alchemist is set in the early 20th century, in a country called Amestris in an alternate-historical Earth with technology dating from early 20th century Europe. In this alternate world, the pseudoscience of alchemy is heavily used, but takes on a further fantastical element than real-life alchemy. Real-world alchemists tried to transmute gold from lesser metals in the real world. In the fictional world of the series, alchemy becomes the science of transmuting matter into different matter through the use of transmutation circles -- based on real-world science, yet also magical, with seemingly infinite uses. Talented alchemists can apply to become the Amestris military's State Alchemists, if they so choose. There are many benefits (and also consequences) to becoming a state alchemist. Against this backdrop, the series portrays the quest of the young Edward Elric, the Fullmetal Alchemist, and his younger brother Alphonse for the legendary Philosopher's Stone. Their adventures lead them to discover the truth about their past and the world they live in.

Edward and Alphonse Elric were children living in the rural village of Resembool in the country of Amestris. Their father, a talented alchemist, had left home when Edward was very young and Alphonse was a baby. Years later, their mother, Trisha Elric, died of an illness.

After their mother's death, the two boys decided to attempt to revive their deceased mother. They studied alchemy with a teacher and then used their father's books and notes that he had left behind to recreate a human transmutation circle. However, this attempt failed, costing Edward his left leg and Alphonse his entire body. In a desperate effort to save his brother, Edward sacrificed his right arm to affix his brother's soul to a suit of armor. After that, Edward's left leg and right arm are fitted with two sets of Automail, a type of advanced prosthetic limb.

A State Alchemist by the name of Roy Mustang arrives during the failed human transmutation in response to letters the boys had sent out seeking information about their father (in the hopes that they could get their father to come home and help them with the reviving of their mom). After seeing their skill at alchemy, Mustang suggests that the way for the two boys to achieve their goals is to become State Alchemists and work for him. Spurred on by the man's proposal, Edward sets out to become a State Alchemist, enabling him to use the resources available to State Alchemists to discover a way to restore what he and Alphonse have lost. The brothers eventually learn of the Philosopher's Stone and set off in search of it as a means to restore their bodies. Along the way they discover secrets about the Philosopher's Stone and find other people who seek it as well.