The 39-year-old beat off competition from the likes of British Lions coach Ian McGeechan, former Scotland coach Frank Hadden and Quins assistant coach Tony Diprose to land the top job at The Stoop.
O’Shea starts his role in March where he will lead a team of existing coaching staff including John Kingston, Colin Osborne and Diprose.
Quins chief executive Mark Evans said: “After a thorough search, the board are delighted to have secured Conor’s services. He combines international playing experience with a proven managerial track record in rugby and elsewhere.”
O’Shea won 35 caps for Ireland before retiring in 2000 and joining the coaching staff at London Irish.
He led the Exiles to the Powergen Cup in 2002 before taking up a role with the Rugby Football Union as director of regional academies.
O’Shea was then named national director at the English Institute of Sport before the Quins eventually lured him back into the front-line of Premiership rugby.
He replaces Dean Richards, who quit following his role in the ‘Bloodgate’ scandal which subsequently saw him landed with a three-year worldwide coaching ban.