Luffy captains the Straw Hat Pirates first through the sea of East Blue and then through the Grand Line. He follows the path of the deceased Pirate King, Gold Roger, from island to island on his way to the great treasure One Piece. On his way his crew grows to have a swordsman, a navigator, a sniper, a cook, a doctor, an archaeologist, a shipwright, and a musician.

During the course of the story, the crew contend with both other less moral pirate crews and the Navy. The latter are the subordinates of the World Government, who apparently seek justice by ending the Golden Age of Pirates. Many background story elements involve the delicate balance of power between the World Government and the world's most powerful pirate crews.

The Grand Line, also known as the Graveyard of Pirates, is a fictional sea and the setting for most of the story in One Piece. It follows an imaginary line that runs north-west to south-east around the world and perpendicular to the Red Line. The Red Line is a stretch of land that circles the globe from south-west to north-east. These two Lines divide the two oceans of the world into four seas: North Blue, East Blue, West Blue and South Blue. There are two Calm Belts, running north and south of the Grand Line. These areas experience almost no wind and ocean currents. The Calm Belts are also breeding ground for huge sea monsters, called Sea Kings in the One Piece world. They are very effective barriers for those trying to enter the Grand Line.

Navigation in the Grand Line is considered to be very difficult. Compasses do not work on the Grand Line because of the nature of its magnetic fields. The islands located in the Grand Line are highly rich in minerals which disturbs the magnetic fields in the area. In order to navigate the Grand Line, a Log Pose, a compass like instrument, must be used. The Log Pose works by locking on to one island's magnetic field and then, once the island is reached, adapting to the next island's magnetic field.

Devil Fruits are a type of fruit which, when eaten, permanently give a special power. There are three categories of Devil Fruit. Zoan fruits allow the user to fully and partially transform into a specific animal. Logia fruits give control over and allow the user "to change their living body structure into the powers of nature". "Everything aside from those is lumped into the Paramecia category." Devil Fruit users can not swim. When even only partially submerged in water, they can't actively use their powers and they temporarily lose their strength.