The spacewalk is the first for Japanese Aerospace Agency (JAXA) astronaut Norishige Kanai, and the fourth for his US counterpart Mark Vande Hei.
The outing began at 7:00 am (1200 GMT) when the duo switched their spacesuits to battery power before venturing out into the vacuum of space. It is expected to last six and a half hours.
Kanai, 41, is a medical doctor and diver who goes by the nickname "Neemo."
He also spent 13 days in the Aquarius underwater lab off the coast of Florida as part of NASAs Extreme Environment Mission Operations (NEEMO) crew in 2015.
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Kanai is the fourth Japanese astronaut to walk in space.
The goal of the spacewalk is to move some components related to the space stations Canadian-built robotic arm, known as Canadarm2, an aging but crucial piece of equipment which has undergone a series of repairs in recent months.
The robotic arm is used to move astronauts and heavy equipment around outside the research laboratory.
"This LEE was replaced during an Expedition 53 spacewalk in October 2017," NASA said in a statement.
"They also will move an aging, but functional, LEE that was detached from the arm during a January 23 spacewalk and move it from its temporary storage outside the airlock to a long-term storage location."
That LEE will be kept at the station as a spare.