The derby pairing of the famous rivals, who last met in the final in 2004, was the highlight of the draw, with ties to be played on the weekend of May 11-13.
St Helens have not failed to reach the semi-finals for 11 years but they will be severely tested by the Warriors, who won 28-10 at Langtree Park on Good Friday.
That was Saints' only defeat in seven matches since caretaker coaches Mike Rush and Keiron Cunningham took charge following the sacking of Royce Simmons.
After being paired with Super League opposition in the first two rounds, last year's beaten finalists Leeds have been handed a trip to Leigh, the only Championship club in the last eight.
In the other ties, Huddersfield landed a home tie against London Broncos while Warrington, winners in 2009 and 2010, face a tricky tie away against Catalan Dragons, where they lost 44-16 on Easter Monday.