Ecuador slumped to a 3-1 defeat in Paraguay but still qualified for a World Cup for just the fourth time -- all this century -- thanks to Uruguay's victory and already-qualified Brazil's 4-0 win over Chile.
Nineteen teams have now qualified for the finals in Qatar later this year, with 13 spots still available.
With Argentina, who play Venezuela on Friday, also already qualified, Peru and Chile will now vie for the fifth-place intercontinental play-off spot from the single South American qualification group alongside Colombia, who emphatically ended a seven-match goalless streak with a 3-0 win over Bolivia.
It has been a remarkable turnaround for Uruguay since a disastrous spell at the end of last year when they lost four matches in a row, conceding 11 goals, scoring just one and slipping to seventh in the 10-team group.
That spelled the end for iconic coach Oscar Tabarez, who spent a record 15 years at the helm and guided the "Celeste" to a World Cup semi-final in 2010 and Copa America title a year later.
But his successor Diego Alonso has won three out of three and taken Uruguay -- winners in 1930 and 1950 -- to a fourth straight finals.
Peru had a glorious early chance to take the lead when Andre Carillo picked out Gianluca Lapadula unmarked 10 yards out but Sergio Rochet dived low to his left to keep out a firm header.
Uruguay were well on top from then onwards and fully deserved their opener.
De Arrascaeta blasted home the rebound three minutes before half-time after Luis Suarez saw a shot crash back off the woodwork.
Federico Valverde almost made it two soon after the break, slamming a stunning swerving 40-yard shot onto the bar.
There were some jangling nerves late on, though, as Rochet was almost caught out by Miguel Trauco's looping mishit cross.
VAR had to check Rochet had kept the ball from crossing the line, and there were barely millimeters in it.