Samardzija handled the hot-hitting lineup fairly well aside from hanging three pitches that the Reds took full advantage of, two of which came with two strikes in an at-bat.
The first bruise was dealt by Xavier Paul in the second inning, a two-run blast on a 2-0 count that was Paul's first homer of his season.
Samardzija then gave up solo shots to Todd Frazier and Miguel Cairo in the fourth inning, surrendering the 2-0 lead Alfonso Soriano gave the Cubs with a two-run homer in the first inning.
"It's unfortunate, especially to jump out to that 2-0 lead and then to give it right back," Samardzija said. "With two strikes, you've got to keep the ball out of the zone. The splitter stayed up for those two pitches, and they took advantage of it. That one stings as a pitcher for sure."
Soriano blasted his way into the record books with his two-run homer in the first frame off Reds starter Johnny Cueto to garner his 1,000th career RBI.
Similar to Friday night's contest, the homer put the Cubs up early. It also made Soriano just the sixth player in MLB history to chalk up at least 1,000 RBIs, 400 doubles, 350 home runs and 250 stolen bases.
"It feels great," Soriano said. "I'm so proud to get 1,000 RBIs because most of my career I batted leadoff. So to have 1,000 RBIs, that's a lot for me. I'm very proud of myself."
That was about the only bright spot for Chicago offensively, as Cueto gave up just two scattered singles over the next seven frames, striking out eight en route to his 16th win of the season.
It was the 11th loss of the season for Samardzija, and the second time in less than a week that the Cubs had fallen to Cueto.
"[Cueto] threw a lot of off-speed stuff," Sveum said. "His changeup was good, he was doing everything with pitching inside and using his off-speed stuff to throttle everything. The guy has a [2.44] earned run average. There's a reason why. He limits the damage."
While the Cubs couldn't scrounge another run off Cueto after the first, they did string together a ninth-inning threat that built some confidence heading into Game 2 of Saturday's doubleheader.
Chicago was down to its final out with Reds closer Aroldis Chapman on the mound, throwing his usual heat. Soriano bounced a single just past the glove of Reds third baseman Frazier for his first career hit against Chapman, keeping the Cubs' hopes alive.
"Finally, I got one hit [off Chapman]," Soriano said with a smile.
Starlin Castro followed by drawing a walk to put two on for Welington Castillo, who dropped a blooper into left field to score Soriano and bring the potential winning run to the plate.
But Chapman then located 98, 99 and 100 mph fastballs on the corners to Joe Mather to quash the late rally.
"In the ninth inning of a day game in August, 95 [mph] is too fast," Soriano said. "It looks like [Chapman] brings all the strength to home, too. He brings everything from the back to home plate."
The Cubs have not won on the road since July 24 at Pittsburgh, but will face Reds rookie Todd Redmond in his Major League debut in the nightcap.