Astronauts Joe Tanner and Heidemarie Stefanyshyn-Piper are making the scheduled spacewalk to connect the wiring on the new addition.
The task must be performed fairly quickly so the electronic components do not get cold.
Two more spacewalks are planned during the 11-day flight, which began on Saturday.
The mission specialists will connect power cables to a truss segment containing solar arrays that a few minutes earlier had been bolted to the ISS.
NASA said the walk was scheduled to last six-and-a-half hours.
Robotic arm
Earlier the astronauts used the shuttle's robotic arm to hand over what is the first major addition to the international space station in more than three years.
The shuttle delivered the giant framework to the space station in a delicately choreographed un-berthing.
It involved the passing from one robot arm to another of a 17.5-tonne construction piece.
The new piece consists of a truss and electricity-generating solar panels that can rotate with the movement of the sun.
The flight marks the first time since the 2003 Columbia disaster that NASA has resumed assembly of the orbiting space lab.
Heat shield okay
There were so few questions with the shuttle's heat shield that NASA opted against its focused inspection, which had been a key aspect of the previous two flights.
That inspection, like another one performed Sunday using a 15-metre boom with sensors at the end, was added after the Columbia accident, which killed seven astronauts in 2003.
Foam debris from that shuttle's external fuel tank broke off during lift-off and struck a wing, allowing fiery gases to penetrate when the craft returned to Earth.
So the lack of an inspection this time allows the shuttle to undock on Sunday instead of the following day, September 18.
That gives the space station an extra day to prepare for its next visitor - a Russian Soyuz that launches September 18.