Boro have spent the season languishing in the lower reaches of the table but a first-half masterclass left Nigel Pearson's men stunned.
Jay Simpson's third-minute opener put the Tigers ahead but Australian frontman McDonald struck twice in quick succession to put the visitors in control and Julia Arca added a third before McDonald grabbed his third on the stroke of half-time.
Anthony Gerrard replied for Hull in the second half but the result was a huge blow to Hull's bid to sneak a top-six finish and gave Tony Mowbray's men only their sixth away win of the campaign.
Simpson struck the first blow for Hull when he latched onto a pass from Richard Garcia and drove a left-footed shot into the top corner from six yards out.
Yet Boro steadied themselves and hit back with a devastating four-goal blast to assume firm control by the break.
Nobody impressed more than former Celtic striker McDonald, who levelled for the Teessiders in the 11th minute when he drilled a right-footed shot into the top corner from 12 yards out.
The home defence began to wobble and Middlesbrough took full advantage as McDonald claimed his second goal in the 13th minute, striking home a powerful right-foot shot from 12 yards to underline his confidence in front of goal.
Remarkably, a third goal arrived for the visitors in the 26th minute when he was afforded the time and space to strike a low right-foot shot into the net from 12 yards.
Hull almost pulled a goal back in the 31st minute when Robert Koren saw a shot tipped round a post by Boro goalkeeper Paul Smith.
The hosts lost defender Liam Rosenior to injury in the 36th minute and he was replaced by Aaron Mclean.
And Boro exposed the weaknesses in the Hull rearguard again as McDonald capped a superb first-half display with his hat-trick goal on the stroke of half-time.
Midfielder Barry Robson crossed dangerously and McDonald arrived to sidefoot the ball home from six yards out.
Hull changed their goalkeeper at half-time, replacing Vito Mannone with Matt Duke between the sticks.
The Tigers went close to pulling a goal back in the 50th minute when striker Matty Fryatt cracked a shot against the crossbar from 12 yards.
Koren then fired narrowly over the crossbar from distance and in the 58th minute Hull took off Garcia and replaced him with Tom Cairney.
Fryatt then fired wide from six yards before Boro lost two players to injury in quick succession.
McDonald and Stephen McManus were replaced by Leroy Lita and Andrew Davies respectively.
And with 21 minutes remaining, Hull cut the deficit when Gerrard collected a pass from Koren and fired into the net from 30 yards.
Boro hit the crossbar late on through Lita as Hull were spared further embarrassment.