The Spaniard , who withdrew from the doubles tournament in Sao Paulo after one match in order to protect his knee from overexertion, was not at his best but still had enough to see off his opponent, ranked 140 in the world.
The 11-times Grand Slam champion, who has slipped to fifth in the world following his injury lay-off but is the top seed in Brazil, wrapped up victory in an hour and 19 minutes.
He came under pressure early in the second set when Souza forced a break point, but it was saved and Nadal went on to break at 4-4 before serving out for victory.
He moves into the quarter-finals - having received a first-round bye - where he faces Carlos Berlocq of Argentina, who downed eighth seeded Spaniard Albert Ramos 7-6(7) 6-4.
"It was an important victory for me," Nadal said. "The conditions are very difficult. The court is very fast, the ball too."
Asked about his injured left knee, he replied: "Today I think it was acceptable, normal. Let's hope it will be the same tomorrow. The important thing is that it (the knee) does not hurt."
Nadal played his first competitive match in close to eight months last week in Chile - the beginning of a three-match run that took him to the final.
Defending champion Nicolas Almagro also kicked off his campaign with a second-round victory, the Spaniard beating Chile's Paul Capdeville 6-4 6-7(3) 6-2.
Almagro has a rich history at the tournament - the second seed has won it a total of four times, including the last three editions.
There was less cheer for third seed Juan Monaco though as the Argentine became the first major casualty of the week, falling to a straight-set 7-5 6-2 defeat to Italian Simone Bolelli.
Round 2 results:
1-Rafa Nadal (Spain) beat Joao Souza (Brazil) 6-3 6-4
David Nalbandian (Argentina) beat Guido Pella (Argentina) 6-4 6-2
Albert Montanes (Spain) beat 7-Pablo Andujar (Spain) 7-5 6-2
Filippo Volandri (Italy) beat 5-Thomaz Bellucci (Brazil) 6-3 6-2
Carlos Berlocq (Argentina) beat 8-Albert Ramos (Spain) 7-6(7) 6-4
2-Nicolas Almagro (Spain) beat Paul Capdeville (Chile) 6-4 6-7(3) 6-2
Simone Bolelli (Italy) beat 3-Juan Monaco (Argentina) 7-5 6-2