Widnes led early on through Charly Runciman's try, but Jermaine McGillvary crossed to put Giants 6-4 ahead.
The visitors dominated from then on, as further tries from McGillvary, Lee Gaskell and Tom Symonds gave them a 14-point lead at half-time.
Stefan Marsh and Rhys Hanbury went over for Widnes, but tries from Aaron Murphy and Leroy Cudjoe sealed Giants' win.
Vikings finished seventh in Super League last season, but they have since seen influential stand-off Kevin Brown join Warrington, while scrum-half Joe Mellor will miss the first two months of the season through injury.
The hosts were punished for their inability to handle Giants' kicking game in the first half, as a number of spilled catches gave Giants good field position to punch over the line.
Huddersfield secured their position in Super League through the Qualifiers last season, but will hope for better this campaign after winning their first first season opener since beating Wigan in 2014.
Widnes head coach Denis Betts told BBC Radio Merseyside: "You could see it unfolding in front of your eyes, we were solid, defended well and controlled the collisions. We scored a really good try, I thought the practice is coming together and then we gave a couple of penalties away and Danny Brough's kicking game caused us problems.
"We were getting left on the floor and suddenly all the things we'd spoken about determination energy and effort we needed through the middle to control their hard-running middle unit went away.
"We're a decent side, run into a couple of things with injuries, but that was a good enough side that should have given us a performance to win the game. We're a miles better side than what we showed tonight."
Huddersfield Giants head coach Rick Stone told BBC Radio Leeds: "It wasn't too bad, we controlled the first half well, made a few little errors and Widens came pretty hard in the second half so there's a little bit to work on. But it's nice to go away and get a win in the first half.
"We had some good intent, played nice and direct and had good intent, some good last tackle options through Danny Brough.
"We came up with some decent plays to score some points and give ourselves a buffer that we needed in the end."
Widnes: Hanbury; Thompson, Armstrong, Runciman, Marsh; Bridge, Gilmore; Dudson, White, J Chapelhow, Whitley, Houston, Leuluai.
Replacements: Heremaia, Cahill, Olbison, T Chapelhow.
Huddersfield: Gaskell; McGillvary, Cudjoe, Mellor, Murphy; Brough, Brierley; Ikahihifo, Hinchcliffe, Ta'ai, Symonds, Ferguson, Lawrence.
Replacements: Wakeman, Leeming, Roberts, Clough.
Referee: Jack Smith.
Huddersfield opened their Super League campaign with a comfortable 28-16 victory at Widnes Vikings.