NASA said the duo repaired hardware critical to the completion of the ISS, a day after their spaceship was cleared to return home.
The astronauts floated up on the ISS to install a spare pump and replace a broken cable reel, according to NASA television images.
"I'm working up a sweat," Mr Fossum said as the duo made preparations to replace the reel for a cable that provides power to the orbiting laboratory's mobile transporter.
Mr Sellers and Mr Fossum, who a day earlier said the spacewalk would be "quite a ballet", moved to another spot on the ISS to install a spare pump module to an external stowage platform.
The astronauts then moved to the shuttle's payload bay to make an equipment swap.
Before replacing the part, the astronauts took a moment to admire the view about 350 kilmoetres above Earth.
"It's like standing in an all-around Imax (3D movie theatre). It's just beautiful," Sellers said.
The pair then slipped back inside the ISS's airlock chamber after completing the nearly seven-hour-long spacewalk.
Discovery docked to the ISS on Thursday in just the second shuttle flight since the Columbia accident that killed seven astronauts in February 2003.
The two astronauts will venture out of the ISS again tomorrow to try out shuttle repair techniques pivotal for NASA's efforts to increase space flight safety.
Officials yesterday declared the shuttle fit to return to Earth on July 17.