The former Bradford Bulls hooker crossed in both halves as Simon Woolford’s classy side vanquished their Yorkshire rivals with a surprise result in Liverpool.
Hull had produced an outstanding defensive display a week ago to win at title-chasing Warrington Wolves but here at Anfield they were shambolic and cut to shreds with alarming ease.
It was the third time this season Lee Radford's side had shipped more than 50 points; when they lose, they tend to lose badly.
Huddersfield, who started the day in ninth place, finished with ten tries as they built on their previous week’s win over Hull KR and continued their bid to push on for the top-five.
Dismal Hull, who hoped to stay level with third-placed Catalans Dragons, were humiliated and left in disarray with a Challenge Cup quarter-final against the French side looming on Thursday.
Full-back Darnell McIntosh and England winger Jermaine McGillvary also scored two tries for Huddersfield who were expertly marshalled by the brilliant stand-off Lee Gaskell and youngster Oliver Russell.
Joe Wardle was a driving force from back-row, powerful prop Suaia Matagi was a menace and Leeming tormented as he always does when replacing O’Brien.
Huddersfield were 20-0 up just after the half-hour mark after ruthlessly taking their chances.
Hull had plenty of pressure but lacked any sort of finesse when it mattered, too many last plays being inadequate and too much dropped ball in promising positions.
Unusually, both Scott Taylor and Joe Westerman spilled under little pressure while - after Marc Sneyd’s 40/20 - Albert Kelly lost possession striving to get over the line.
Initially, Giants were not without their own errors, too, McIntosh seeing a restart bounce dead off his leg and Gaskell ushering a forward pass.
However, as the rain came down, they had a sharper edge and a far more dominant defence.
Joe Wardle got their first try early on when Hull full-back Jamie Shaul allowed Oliver Russell’s chip to bounce and it wickedly eluded him.
When McGillvary chased hard to earn a drop-out, their young left-edge combined wonderfully - Russell feeding McIntosh whose long pass saw Innes Senior expertly nudge back inside for Jake Wardle to score.
When Mark Minichiello caught Gaskell high, O’Brien dummied over from close range, bumping off both Taylor and Westerman between the posts on his 100th Super League appearance.
McIntosh added their fourth with Russell adding a drop goal to his earlier two conversions.
All Hull - who saw prop Josh Bowden make his comeback from ACL surgery - could must was Sneyd’s penalty on the stroke of half-time.
However, they got worse in the second period.
After Joe Wardle did brilliantly to bully Shaul back over the line to concede a drop-out, O’Brien dummied over again from close range, Hull clearly having learned no lessons whatsoever from the first half.
McIntosh splintered Sneyd and Minichiello for his second try before Leeming darted out of dummy-half for Alex Mellor to bundle over.
Aaron Murphy found acres of space to speed down the right to supply McGillvary for another try before the England winger collected Gaskell’s lofted chip to repay the favour.
Hull rarely looked like even threatening Huddersfield’s line. When they finally did, Sika Manu breaking down the middle on the last tackle in the 76th minute, Senior raced across to drag him down just short, epitomising Giants’ spirit here.
Instead, McGillvary added his second when Gaskell produced yet another assist, his cut-out pass leaving Hull flapping once more.
Hull FC: Shaul; Naulago, Connor, Griffin, Buchanan; Kelly, Sneyd; Taylor, Washbrook, Paea, Hadley, Minichiello, Westerman. Substitutes: Bowden, Green, Manu, Fash.
Huddersfield Giants: McIntosh; McGillvary, Turner, Turner, Jake Wardle, I Senior; Gaskell, Russell; English, O’Brien, Matagi, Joe Wardle, Mellor, Murphy. Substitutes: Leeming, Clough, Lawrence, Ta’ai.
Referee: Liam Moore (Leeds)