O'Donoghue, who left NBC Universal International in January, has been appointed managing director of ITV Studios, working with former Channel 4 director of television Kevin Lygo in the division's new senior management team.
In her new role, O'Donoghue will lead the company's commercial strategy, including responsibility for production management, rights management and business affairs.
In its recent financial result statement, ITV said that revenue at ITV Studios was down 10% year-on-year to £205m over the nine months to September 30.
Internal revenue from making shows for ITV channels was £181m, up from £176m last year, but the broadcaster noted the pressing need for "creative renewal".
O'Donoghue and Lygo will now be tasked with generating more hit programme formats for ITV channels and international broadcasters to drive up revenues.
In 2005 ITV produced 65% of its own programmes, but that has dropped to just 47% today, while its last major hit show produced in-house was Dancing On Ice.
Discussing O'Donoghue's appointment, ITV chief executive Adam Crozier said: "A key part of our five-year strategy is to build a stronger content business and to develop the relationship between ITV Studios and our broadcast business.
"Denise has a fantastic track record as an entrepreneur creating great content and commercial value. She and Kevin Lygo will make a formidable team, spearheading the development of ITV Studios."