Saints, who fell just short of extending their winning Super League run to a club-record 13, paid the price for opting to rest Sean Long as they crashed to their first defeat since October.
Huddersfield, who pushed St Helens close in their previous meeting in March, belied their lowly League position to outplay the leaders, scoring three tries to two in a memorable encounter.
Saints, who had 18-year-old Matty Smith making his full debut in place of Long and started with two other Great Britain internationals, Leon Pryce and Keiron Cunningham, on the bench, were out of sorts from the start.
Without their big guns they lacked a cutting edge, with the Giants coping easily with their stereotypical attacks.
Huddersfield, who gave a debut to former St Helens prop Keith Mason, were the more inventive side throughout, with Robbie Paul prompting and probing to good effect and acting captain Brad Drew keeping the visitors pinned back with some clever kicking.
The home side took a deserved lead when Paul and Drew combined with stand-off Paul March to get centre Michael De Vere running through a gap to touch down on eight minutes.
De Vere converted his own try and the Giants had chances to extend their lead, with wingers Stuart Donlan and Martin Aspinwall both dropping passes with the Saints line breached.
St Helens coach Daniel Anderson responded to his side?s struggles by sending on Cunningham after 25 minutes, with Pryce entering the action six minutes later.
And it was Pryce who created Saints? try, charging down Drew?s attempted clearance kick and re-gathering to send centre Willie Talau over.
Skipper Paul Sculthorpe, who had opened his side?s account with a penalty just after the re-start, added the conversion to edge them in front for the first time but Saints? lead lasted only six minutes.
De Vere levelled the scores with a penalty and Huddersfield went back in front on 56 minutes when man of the match Drew made a half-break and was quickly in position to take March?s pass and sent Donlan over for the Giants? second try.
De Vere kicked his third goal but Sculthorpe did likewise to keep his side in touch after Paul Smith had been penalised for a high tackle on James Graham.
The decisive moment came on 61 minutes when March followed up his own grubber kick and pounced on a handling error from Vinnie Anderson to claim the vital try.
Drew hit the woodwork with the conversion attempt but put over a drop goal to open up a nine-point gap.
Saints had the final say when teenage prop Graham took Sculthorpe?s pass to crash over for a try which Sculthorpe converted but Huddersfield held on in a nervous finale to secure a precious win.
Huddersfield: Reilly, Aspinwall, Evans, De Vere, Donlan, March, Paul, Crabtree, Drew, Gannon, Nero, Jones, Mason. Replacements: McDonald, Grayshon, Hemingway, Smith.
St Helens: Wellens, Gardner, V. Anderson, Talau, Meli, Moore, Smith, Fozzard, Roby, Graham, Sculthorpe, Hooper, Wilkin. Replacements: Pryce, Cunningham, Fa'asavalu, P. Anderson
Huddersfield: (6) 19. Tries: De Vere, Donlan, March. Goals: De Vere 3. Drop Goals: Drew.
St Helens: (0) 16. Tries: Talau, Graham. Goals: Sculthorpe 4.
Referee: Phil Benson (Bolton)