Second-half strikes from Maxi Rodriguez and Ignacio Scocco gave the Argentinian champions a healthy cushion going into next Wednesday's return leg at the Estadio Independencia in Belo Horizonte.
An atmosphere of anxiety among the supporters at a packed Estadio Marcelo Alberto Bielsa seemed to transmit itself to the Newell's players in the first half as they struggled to play their best football.
After the break, however, Atletico sat back as they were more concerned with not conceding and Newell's took advantage.
Midfielders Diego Mateo and Lucas managed to nullify the threat of Ronaldinho, as the former Barcelona and AC Milan playmaker was unable to recreate the magic of old.
It was not until the 61st minute though that the hosts opened the scoring, with former Liverpool midfielder Maxi heading a Victor Figueroa cross into the back of the net.
Maxi had another opportunity to score in the 73rd minute, when he ran into the left side of the box and keeper Victor rejected his shot before a defender stopped Figueroa's follow-up attempt close to the line.
Atletico forward Jo was denied a goal in the 75th minute as he was offside after Newell's keeper Nahuel Guzman saved a header.
Newell's finally doubled the lead five minutes later, with a tremendous free-kick by Scocco, his sixth goal of the Libertadores.
Maxi told Fox Sports: "Winning was the important thing tonight, as was being strong at home.
"Atletico Mineiro is one of the best teams in the competition. There are 90 minutes left yet, but what we achieved tonight is very, very important. We must keep up this form."
Scocco added: "We planned to score as many goals as possible.
"It was a very nice match because Atletico Mineiro play well but also let you play. In the second half, we managed to score and if you want to make the difference in football, you have to score the opportunities you have."
Ronaldinho, meanwhile, is hopeful of overturning the deficit and making it into the final.
He said: "We'll do our best. We did not expect this result, but this is not the end."