A bright Spireites start saw them take a deserved lead, but a strong Hull City comeback turned things round to give the Tigers a 3-1 win.
The hosts took the lead after 19 minutes, when Ian Evatt headed home Tendayi Darikwa's precise centre with power, the goal deserved after a energetic Spireites opening.
The Spireites couldn't keep their lead until the break however, as Harry Maguire headed home a corner, the teams level at the half. Sharp from the start of the second period, the Tigers took the lead when Andy Robertson finished well from inside the box.
The Tigers grabbed a third when substitute Dame N'Doye was put in on goal, Tommy Lee did well to sprawl and halt his progress but the ball fell to fellow substitute Calaum Jehraldo-Martin who steered into the unguarded net from inside the box.
Hull had more of the ball in the opening stages but it was Chesterfield who came closest to scoring when new signing Sylvan Ebanks-Blake saw his near post effort saved by Allan McGregor.
The Spireites came close to opening the scoring when the ever-dangerous Tendayi Darikwa attempted a cut back from the byline that was deflected and tipped over the bar by the keeper. The following corner brought the opening goal after Ian Evatt’s powerful header found its way into the back of the net.
Parity was almost restored soon after, but unlike Evatt, Curtis Davies couldn’t find the target with a free header. Hull continued to control possession but couldn’t break down a sturdy Spireites back four.
With half time approaching the visitors found an equaliser through another headed goal, this time from Harry Maguire who managed to lose his man and head home.
The second half was barely five minutes old when the Championship outfit took the lead for the first time when left-back Andrew Robertson found the net with a powerful finish from a tight angle after being sent through by Sone Aluko.
Hull could have gone further ahead when David Meyler found himself in acres of space in the Chesterfield box but he fired wide.
The visitors had a grip on possession as the second half wore on with substitute Dame N’doye firing over Lee’s bar after 73 minutes.
The Tigers then put the game to bed with just under 15 minutes to go when youngster Calaum Jahtaldo-Martin found the back of the net with the aid of a deflection following good work from fellow sub Abel Hernandez.
Hull almost grabbed a fourth goal through substitute Brian Lenihan after he fired over the bar from close range when he met a Conor Townsend cross on the volley.
The hosts continued to battle away against a well-drilled Hull team who ultimately proved to be too strong in the second half.
Chesterfield: Lee (gk) - Jones (Harrison 89'), Hird (Orrell 75'), Evatt, Darikwa - Gardner (Ariyibi 68'), Morsy (c), Banks (Donohue 78'), O'Shea (Raglan 57') - Clucas, Ebanks-Blake (Gnanduillet 68')
Subs not used: Humphreys, Cairns (gk), Onovwigun, Orrell, Dieseruvwe, Simons
Hull City: McGregor (gk) (Jakupovic 46'), Bruce (Dixon 46'), Davies (Chester 46'), Meyler (Clark 79'), Brady (Jahraldo-Martin 66'), Maguire, Jelavic (N'Doye 62'), Dawson (c), Aluko (Hernandez, Robertson (Townsend 79'), Elmohamady (Lenihan 78')
Chesterfield: Evatt 19'
Hull City: Maguire 38', Robertson 51' Jahraldo-Martin 76'