Aston Villa loan star Philippe Coutinho, Leeds' Raphinha and Newcastle's newest recruit in midfield Bruno Guimaraes all played a part in the victory.
The win means the Selecao top the South American qualifying group with no defeats in 15 games.
It also means they extended their unbeaten home record in World Cup qualifiers to 61 matches.
Raphinha opened the scoring, but it wasn't all rosy for the Leeds winger, who emerged as a late target for West Ham during the January transfer window but a deal never came to fruition.
The 24-year-old scored one, had another chalked off, and also struck the post in the clash.
Coutinho, who's had a great start to life at Villa following his loan transfer from Barcelona, got a deserved second for the home side just after the hour when he placed a sumptuous shot into the top corner of the net from long range.
Ajax winger Antony got Brazil's third with four minutes left when he curled a left-foot shot past a helpless keeper.
Guimaraes, one of Newcastle's new signings, came off the bench to set up the winner for Real Madrid winger Rodrygo, who tapped home a late fourth for the five-time world champions.
For Paraguay, the defeat ended their qualifying hopes for Qatar and further cemented Brazil's position as one of the favourites to lift the trophy in December.
They have yet to win any of their first five games under coach Guillermo Barros Schelotto and sit second from bottom of the 10-team group with 13 points from 16 games.