Ross is the latest big name to cameo in the show, which has previously featured Ben Stiller, Michael J Fox, Selena Gomez, Slash, Jamie Oliver, David Mitchell, Damian Lewis and Gary Lineker. Tim Curry will also appear in Ross's episode.
The chatshow host will play a Ducky MoMo salesman, in the show's third season.
Series creator Jeff 'Swampy' Marsh said: "Dan Povenmire [co-producer] and I shared our love of British comedy when we were creating Phineas and Ferb; it was one of the things that bonded us creatively.
"Having had the opportunity to work with some of the best of British talent over the first few seasons of Phineas and Ferb has proved immensely popular with the fans and is incredibly exciting for us.
"Adding the iconic Jonathan Ross to that list is just indescribably thrilling. He is loved by kids and adults across the UK and is one of the most talented and funny people anywhere. I have personally been a fan of his since I first moved to the UK for both his TV and radio work and when I heard that he was going to lend his voice to our show, I was quite frankly a bit giddy!"
Ross's episode will premiere in early 2013 on Disney XD.
"I am a huge fan of Phineas and Ferb, and so are my teenage kids, so I absolutely jumped at the chance to be part of such a brilliant and well-written comedy series," said Ross.
"It's a show that both adults and kids of all ages can enjoy together and I can't wait for everyone to see my episode."
Phineas and Ferb is based around the adventures of Phineas and his English stepbrother Ferb - who set out to conquer boredom and make every day of their 104-day summer holiday count, much to the annoyance of their older sister Candace (Ashley Tisdale).