Denis Cheryshev's own goal compounded Russia's misery 13 minutes later, with Smolnikov's dismissal - for a second yellow card issued after a foul on Edinson Cavani prior to half time - all but ending hopes of a comeback.
And while La Celeste dominated for large swathes in the second half, it took until the final minute to add to their lead, when Cavani slotted home from close range to put added gloss on an already polished performance.
Coach Stanislav Cherchesov had made two more changes but they also backfired spectacularly, with Igor Smolnikov sent off in the 36th minute after a second booking, and Fyodor Kudryashov equally overworked in defense.
TALKING POINT - Might Oscar Tabarez stick with this more expansive shape for the last 16? This might have been a sign of things to come.
Yet the hosts are brimming with confidence having made it past the group stage of a World Cup for the first time since the Soviet Union lost to Belgium in the last 16 in 1986. But on the pitch there was very little of the dynamism we saw from Russia's players in their opening two victories.
Both teams were already assured of spots in the knockout round, but Uruguay's victory put it at the top of Group A and looking toward a match in Sochi on Saturday against the second-place finisher from Group B. Subs - Smolov 6, Fernandes 5, Kuzyaev 4. But Luis Suárez opted to go to the far post and put Uruguay up 1-0 over Russian Federation.
Russian Federation finished second in Group A after suffering their first World Cup defeat at the hands of Uruguay in Samara on Monday and will next face Group B winners and 2010 champions Spain in Moscow on Sunday. Cheryshev sends a half-volley towards goal from the edge of the box, but it's straight at Muslera, who makes the save.
Suarez scored in that match, and thwarted Russian Federation in this one, too. His strike picked up a huge deflection, completely wrong-footing Akinfeev.
Uruguay got off to a positive start when Matias Vecino whistled a long-range effort just wide of Akinfeev's right post with less than two minutes gone as the South Americans served warning of their intent.
A song by comedian Semyon Slepakov went viral just before the tournament, poking fun at Russia's poor form and suggesting players needed Chechnya's authoritarian leader, Ramzan Kadyrov, as coach for extra motivation.
Uruguay would have had a third soon after if not for a fine save from Akinfeev, who prevented Bentancur celebrating his 21st birthday with a goal.