Fryatt, who has now scored six goals in seven appearances for the Tigers following his permanent switch from Leicester last month, gave the visitors a flying start with an opening goal in the fifth minute.
Mclean, who also joined Hull for an undisclosed fee last month, from Peterborough, tucked home his first for the club from close range early in the second half and from then on the result was not in doubt.
Scunthorpe's Joe Garner headed his first goal for the club following his recent arrival on loan from Nottingham Forest in the 55th minute, but Fryatt converted a 73rd-minute penalty and Mclean fired his second from Nick Barmby's assist in the 81st minute.
Fryatt lashed home his third following substitute Tijani Belaid's corner in the 89th minute to leave the Iron, without a win in any of their last 11 home league games, second from bottom in the table.
But while Scunthorpe's only win this season at Glanford Park came back in August, Hull stretched their unbeaten away run in the Championship to 10 matches and have lost only one of the 15 games since a 1-0 home defeat to their Humber rivals in November.
Fryatt struck his fourth goal in his seventh game for Hull following good work from Robert Koren on the left side of the penalty area, lashing home a low drive into the bottom corner.
Scunthorpe held their own in terms of possession but, save for Bobby Grant's sliced shot and Michael Nelson's header from Mark Duffy's corner, they failed to carve out a chance of any sort until Duffy's thumping volley was turned away by Hull goalkeeper Brad Guzan in the 31st minute.
Nelson volleyed just off target for Scunthorpe soon after and then Lee Miller mis-hit his shot inside the area following Eddie Nolan's free-kick as Hull defended their slender lead.
The visitors had soaked up everything Scunthorpe had to offer during the first half and then broke out to extend their lead five minutes into the second period.
Mclean reacted quickest when Nelson's error put Scunthorpe in trouble and broke his Tigers duck from six yards.
But the home side were thrown a lifeline in the 55th minute. Hull defender Paul McShane fouled Grant out wide on the left and from Duffy's free-kick Garner headed home his first goal in his second game for the Iron.
Mclean skewed a shot from the edge of the area wide and Koren was wayward with his 25-yard shot, while Duffy saw his effort from similar distance blocked by Hull defender James Chester at the other end.
Hull defender Andy Dawson secured his side a penalty in the 73rd minute when he was brought down by Grant in the penalty area and Fryatt stepped forward to fire his fifth goal in seven games for the Tigers from the spot.
Barmby, a second-half substitute for Tom Cairney, set up Mclean for Hull's fourth in the 81st minute, clipping the ball inside from the left edge of the area for the former Peterborough forward to arrow the ball into the bottom corner from 12 yards.
Michael Collins had a shot blocked as Scunthorpe refused to roll over, but Fryatt slammed home his hat-trick goal in the 89th minute following Belaid's corner.