Khawaja has been a perennial bridesmaid on recent tours - picked in the party, but never actually getting a Test.
He made his debut against England at the SCG back in 2011, but played his last Test in December of that same year.
There will be pressure on Khawaja to get it right though, with David Warner likely to be back in the frame for the third Test at Old Trafford.
But at least it's a chance for the 26-year-old, who missed the chance of a game in India earlier this year after being one of four players stood down for failing to complete an assignment tasked by former coach Mickey Arthur.
There was originally a suggestion Cowan would have one more match to prove himself but new coach Darren Lehmann has stressed a desire to play aggressive cricket, and Khawaja is the positive selection.
Lehmann has made it clear he wants runs, and Cowan made a golden duck and 14 at Trent Bridge.
Meanwhile, Harris is playing his first Test since last year.
The pitch has more grass on it than the dry first Test wicket at Trent Bridge, and the 33-year-old is seen as one of the most dangerous outswing fast bowlers in the world.
Harris, Peter Siddle and James Pattinson will form the attack, with Starc missing out.
Harris is thought to have the better control for Lord's and its infamous slope - which can become a graveyard for errant quicks.
Australia has a tremendous record at Lord's, with 14 wins overall and only two losses since 1934.
"It is definitely relevant. It feels like a home ground for us," said Clarke.
Meanwhile, England have made one change bringing Tim Bresnan to replace Steven Finn.
Team: Shane Watson, Chris Rogers, Usman Khawaja, Michael Clarke (capt), Phil Hughes, Steve Smith, Brad Haddin, Ashton Agar, Peter Siddle, Ryan Harris, James Pattinson.