With the game tied at 2-2, the 38-year-old Votto, a Toronto native, hit a one-out, 2-0 curveball down the line off Blue Jays right-handed reliever Yimi Garcia (0-3).
The blast was Votto's first of the year. The six-time all-star first baseman was activated from the COVID-19 injury list before the series opener Friday.
He finished the series 3-for-11 with a first-inning walk in the finale. Votto has made 12 career visits to Toronto and has 11 hits in 44 plate appearances, including four homers.
Toronto (22-19) aimed for its first series sweep of the season before 42,323 at Rogers Centre against the last-place Reds (12-28).
Reds closer Art Warren enjoyed a 1-2-3 ninth inning for his second save. Cincinnati reliever Alexis Diaz (2-0) picked up the win for his two innings of work.
Toronto starter Yusei Kikuchi struggled in the first. He faced eight batters and threw 37 pitches as Cincinnati grabbed a 2-0 lead.
Kikuchi walked three of the first four batters he faced to load the bases. Aristides Aquino then smacked a two-out, ground-rule double down the left-field line.
Kikuchi settled down to retire 10 in a row until Reds catcher Aramis Garcia led off the fifth with a single to left field.
The Blue Jays starter lasted 4 1/3 innings, struck out seven, walked three and allowed two hits.
Toronto pulled to within 2-1 in the second because of a leadoff double from Santiago Espinal and a run-scoring single to right field from Matt Chapman.
The Blue Jays tied the game in the third. A pitch hit George Springer on his left elbow. He moved to second on a wild pitch and took third base on Vladimir Guerrero's long fly ball to centre.
Springer scored on Bo Bichette's ground ball to Cincinnati shortstop Kyle Farmer.
Springer made a fine running catch in the right-centre gap on a shot hit by Farmer in the sixth.
Cincinnati starter Graham Ashcraft made his major-league debut, lasting 4 1/3 innings. He yielded two runs on four hits, walked two, struck out three, and delivered a wild pitch and hit Springer.
SANTIAGO'S STREAK -- Espinal's second-inning double extended his hit streak to 15 games, the longest active streak in the MLB.
In his impressive run, the Blue Jays' second baseman has gone 29-for-52 (.365).
NEXT UP -- The Blue Jays begin a two-game set in St. Louis against the Cardinals (23-18) on Monday, the first of six straight on the road. Toronto right-hander Jose Berrios (3-2) will face fellow right-hander Miles Mikolas (3-2) in the series opener. Berrios stopped a two-game personal losing streak in his last outing with a 3-0 shutout victory against the Seattle Mariners last Tuesday.