The Cubs won for the eighth time in nine games despite not getting a hit in the 10th.
Catcher Willson Contreras started the winning rally off Jackson Stephens (2-2) with a walk and took second on a wild pitch. After Stephens struck out Victor Caratini, the Reds intentionally walked Ian Happ.
Addison Russell appeared to make the second out, but first baseman Joey Votto lost control of the ball as he touched the bag. The initial call was overturned on a crew chief's review and Votto was charged with a fielding error.
After Stephens threw ball one to Bote, the Reds moved in Adam Duvall from left field to be the fifth infielder. The move did not come into play as Bote looked at a high pitch for ball four and gave Chicago its third walk-off win of the season.
The Cubs took two of three from the Reds in the teams' first series with nothing but one-run games since May 1967.
Duvall prompted extra innings when he hit a game-tying homer off Brandon Morrow in the ninth. After Morrow blew his second save and allowed his second homer in the last two season, the Cubs left the bases loaded in the ninth against Jared Hughes.
Before Morrow's hiccup and Bote's walk, the Cubs took a 5-4 lead on a two-run single by Javier Baez with one out in the seventh off David Hernandez.
Baez upped his RBI total to 65.
Russell drove in the first three Chicago runs with a double in the second and a groundout in the fourth.
Billy Hamilton stole two bases and scored two runs for the Reds, who were denied their sixth straight series victory.
Hamilton reached base in nine of 12 appearances and on Sunday he stole his 20th and 21st bases of the season, marking the fifth time he swiped at least two bases. Both times, Hamilton scored after stealing second.
He scored Cincinnati's first run on Jose Peraza's single to center with two outs in the third and then scored the fourth run two innings later while capitalizing on errors by catcher Contreras and center fielder Albert Almora Jr.
Contreras threw the ball into center field trying to throw out Hamilton for the first error. Almora made the second error as his throw short-hopped the plate as Hamilton tumbled in to make it 4-3.
Eugenio Suarez hit a two-run homer in the fourth off Cubs starter Jon Lester, who allowed four runs on six hits in 6 1/3 innings.
Luke Farrell (3-3) breezed through an eight-pitch 10th and notched the win.
Reds starter Luis Castillo allowed three runs on six hits in four innings.
--Field Level Media