The Australian striker scored all three goals in the first half as 'Boro fell behind early at KC Stadium before firing 4-1 ahead and then conceding a consolation goal to the Tigers to move up to 17th on the table.
Jay Simpson put the home side ahead in just the third minute before McDonald leveled eight minutes later with a well-struck shot into the top corner from about 12 yards. He grabbed his brace two minutes after his first with another solidly hit shot prior to Julio Arca making it 3-1 in the 26th minute.
McDonald completed his hat-trick on the stroke of half-time when he side-footed home from close range before Anthony Gerrard got one back for Hull with just over 20 minutes remaining.
McDonald's performance, which produced the first treble in the opening half by a Middlesbrough player in 22years, was praised by Teessiders boss Tony Mowbray.
"Whether he scores or not, Scott works his socks off for the football team," Mowbray told the cllub's official website. "He's a centre-forward who I've asked to plays slightly differently from the way he was used to playing with Celtic.
"He's having to work very much harder for the team and he's taken that on without any moaning and groaning. He obviously enjoys scoring goals and he'll have enjoyed that today."
He added at the post match press conference: "We went forward well and asked a lot of questions of their defenders in the first half, and McDonald took his goals exceptionally well."
'Boro next meet Coventry City tomorrow night and have now surely staved off relegation as they now sit 12 points clear of the drop zone.