Danaher, 32, will captain the side from the back row alongside Jamie Gibson and Chris Hala'ufia.
Exiles' record try scorer, Topsy Ojo, will start in the back three along with Sailosi Tagicakibau and Anthony Watson, who will start a Premiership match for the first time.
London Irish Director of Rugby Brian Smith said: "Sunday will mark a great mile-stone for one of London Irish's finest warriors when Declan Danaher pulls on the London Irish jersey for the 250th time.
"It's an incredible feat of endurance and courage. It will be a tough afternoon for Dec and the boys; we can expect a thorough examination in all departments as Harlequins have a strong pack and some extremely dangerous backline players.
"Whilst we have a healthy respect for our opponents, we have faith in each other and the belief that we can beat any team in this league."
Irish will be looking for their fourth straight win in all competitions going into Sunday's mouthwatering clash.
They sit top of their group in the Amlin Challenge Cup thanks to big wins over Begles Bordeux and Mont-de-Marsan, and thrashed Northampton Saints 39-17 at the Madejski Stadium in their last Premiership match.
London Irish team to face Harlequins: 15. Anthony Watson; 14. Topsy Ojo; 13. Jonathan Joseph; 12. Guy Armitage; 11. Sailosi Tagicakibau; 10. Ian Humphreys; 9. Tomás O'Leary; 1. Max Lahiff; 2. David Paice; 3. Halani Aulika; 4. Bryn Evans; 5. Matt Garvey; 6. Declan Danaher (Captain); 7. Jamie Gibson; 8. Chris Hala'ufia.
Replacements: 16. Scott Lawson; 17. Cai Griffiths; 18. Leo Halavatau; 19. Kieran Low; 20. Ofisa Treviranus; 21. Alex Gray; 22. Steven Shingler; 23. Darren Allinson.