The Spireites were good value for a first-half lead, courtesy of Jay O'Shea, only for Kortney Hause to level matters in first-half stoppage time.
Both sides went close after the interval but Kuffour's brilliantly improvised finish consigned the visitors to a third successive league defeat on their travels.
Paul Cook's men deservedly went ahead in the 29th minute as O'Shea evaded a challenge on the corner of the box before unleashing a ferocious strike which burst through the hands of Jordan Archer.
And O'Shea was unlucky not to double his tally as the MK Dons loanee rattled the underside of the crossbar.
On the stroke of half-time, though, Wanderers snatched a scruffy leveller, as Josh Scowen's corner prompted an almighty scramble and Hause bundled over the line.
After the break, Dean Morgan raced onto Kuffour's clever ball but screwed his effort horribly wide.
But it mattered not as Wycombe completed the turnaround in the 54th minute, as Kuffour, on the turn, deftly flicked over Tommy Lee and into the net.
Chesterfield pushed for an equaliser but substitute Brennan Dickenson was foiled by Archer while Jack Lester stabbed wide.