The crowd of 14,486 at the new stadium at Riverview Park set a Cactus League record.
Samardzija, the Cubs' No. 1 starter last season, allowed a walk and a single to start the game, but then got Paul Goldschmidt to fly out. He then struck out Aaron Hill and Eric Chavez to end the first inning.
The right-hander said the Diamondbacks "really make your work. ... They don't get themselves out. They have an excellent lineup. It was good to open up with them.
"To work out of that first-inning jam and get a double-play was just about everything I wanted to do," he added.
Samardzija allowed a single to Miguel Montero in the second inning.
"He's capable of winning the batting title," Diamondbacks manager Kirk Gibson said of Prado. "He really is."
Cubs reliever Jose Veras gave up two runs in the sixth.
HOME, SWEET HOME
The Cubs' opened their new stadium in grand fashion. A sellout, the game drew a Cactus League record of 14,486, including thousands either standing or lounging in the lawn beyond the outfield fence. The pregame celebration included fireworks and remarks by Mesa Mayor Scott Smith.
"It was exciting" Samardzija said. "I think this was the first time the Cubbies had fireworks, ever."
Diamondbacks pitcher Bronson Arroyo said: "It's always nice to pitch before a big crowd. I've been out in Goodyear (for Cincinnati) ... not a whole lot of crowds out there.
Cubs Hall of Famer Fergie Jenkins led the crowd in singing, "Take Me Out to the Ball Game" in the seventh inning.
Diamondbacks: Arroyo, a recent acquisition by Arizona, allowed two runs in three innings in his spring debut.
"I felt pretty average, not horrible but not great," said Arroyo, who indicated the main benefit was that he and Montero, the catcher, were able to start to get to know each other.
"A good outing for him," Gibson said.
But Arroyo indicated he's a few days behind other pitchers, and he's unsure whether he'll be ready for the diamondbacks' first games, March 22-23, in Australia.
New Cubs manager Rick Renteria acknowledges that "all eyes" this spring will be on infielder Starlin Castro, the young star coming back from a subpar season.
"I hope to see a young man who is trying to put himself back on the level ... of a few years ago, That kid is still in there," Renteria said. "I just hope he comes out and starts to enjoy himself a little more again, play the game the way he's capable of by maybe releasing some of the anxieties he may have had."
Castro went 2 for 2 with a double and an RBI on Thursday.
Diamondbacks outfielder Cody Ross is making great progress from an "extreme injury" to his hip late last season, Gibson said. Could he be ready for the opening games in Australia? "Possible, but that's probably a rush."