Sunderland have enjoyed an impressive first season back in the Premier League, but this was a dismal defeat for Regis Le Bris' side.
Ben Waine capitalised on poor marking to head the 28th-minute winner, sending Port Vale into the FA Cup quarter-finals for the first time since 1954.
Jon Brady's side appear destined for relegation, but they beat second-tier Bristol City in the fourth round and produced an even more remarkable performance to make a mockery of the 56-place gap between them and Sunderland.
The giant-killing will delight their most famous fan, pop star Robbie Williams, who grew up near their Vale Park stadium in Burslem, and is now the club's president.
It was also a memorable moment for Brady, a 50-year-old Australian who replaced the sacked Darren Moore in January and has spent his managerial career in the shadows with Brackley and Northampton.
Earlier on Sunday, Fulham suffered a shock defeat against Championship side Southampton to reach the FA Cup quarters. Read more about that here.
Later in the day, Leeds host second-tier Norwich, while West Ham meet Brentford on Monday.
Arsenal, Chelsea, Manchester City and Liverpool booked their quarter-final places on Friday and Saturday.