D'Urso was first promoted to the Football League in 1994; five seasons later he was promoted onto the Premier League list. In 2001 he was nominated for FIFA status, officiating in a full international in May 2004 when the Republic of Ireland vs Nigeria.
On 29 January 2000 while refereeing the game between Manchester United and Middlesbrough, D'Urso awarded Middlesbrough a penalty kick when Juninho was tackled by Jaap Stam. Upon awarding the kick, six Manchester United players (Roy Keane, Nicky Butt, David Beckham, Jaap Stam, Ryan Giggs and Denis Irwin) chased D'Urso to object to the decision; the resulting image was freely circulated by the media. D'Urso said of the incident: "It was my first season in the Premier League, my first time refereeing Manchester United and my first time at Old Trafford. With more experience I would have stood my ground. I kept saying 'go away', but the further back I walked the more they walked on. A more experienced referee would not have retreated. But there are no grudges. I've refereed Roy Keane on a number of occasions since without a problem."  Several players, notably, Keane and Stam, have since voiced their regret of the incident. D'Urso booked Keane for dissent shortly after the incident.
The Football Association suspended D'Urso for 28 days from 27 August 2004 when he failed to send off Blackburn Rovers captain Barry Ferguson after showing him two yellow cards. D'Urso vowed to carry on with his refereeing career. D'Urso appealed, successfully, against the decision to relegate him from the Select Group but he was not selected for a single Premiership match in the 2005–06 season.
During a League 2 game between Exeter City and Morecambe on 18 February 2014, David Wheeler was bought down by a Morecambe defender. D'Urso instantly pointed to the penalty spot to award Exeter a shot from 12 yards. This decision cause problems for both teams as Exeter City midfielder Matt Oakly punched out at Morecambe striker Jamie Devitt. Instantly, Devitt headbutted Wheeler which resulted in him being sent off. However D'Urso failed to send off Matt Oakly for his previous punch. With the score at 1-1, and into the final seconds of stoppage time, John O'Flynn looked ready to take the penalty, as D'Urso was talking to an official over on the far side. After his briefing, D'Urso awarded Morecambe the free kick, claiming that Wheeler had dived and he was booked before play was restarted. D'Urso was being escorted off by the stewards as Exeter and Morecambe fans raged into a vibe of boo's after the 1-1 draw. Following these controversies, a Facebook page set up called 'Andy D'Urso, the worst referee to ever step onto a football pitch'.
- "D'Urso feared Old Trafford pushover". BBC Sport. 31 January 2000. Retrieved 16 February 2007.
- "Andy D'Urso: Abuse, snarls and sandwiches – a day in the life of a referee". OfficialSports.co.uk. Retrieved 14 November 2006.[dead link]
- "D'Urso is suspended". BBC Sport. 1 September 2004. Retrieved 14 November 2006.
- "D'Urso on comeback trail". BBC Sport. 13 September 2004. Retrieved 14 November 2006.
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