I assume you arrive at Guarulhos, which is the main international airport of Sao Paulo. It's quite time consuming to get from Guarulhos to downtown Sao Paulo, so, if your hotel is close to the airport, you should think twice about venturing into town.
That said, a taxi will set you back about 150R$, currently about 40USD, while public transport, which will be a bit cumbersome, will cost as little as about 8R$ (2USD).
It's difficult to suggest only one thing in Sao Paulo, but you can take your pick from the following:
- Eat and drink in Liberdade, the Asian suburb of Sao Paulo and smack in the middle of town.
- Eat and drink in Vila Madalena, a young and hip suburb. This is slightly out of the way, though.
- Eat and drink in Pinheiros, perhaps even hipper than Vila Madalena, and where many of the galleries are located.
However, if you're 'just' looking for a genuine Paulista experience, you could also find a neighbourhood lanchonete (snackbar) close to your hotel, and share a few liter bottles of beer with plates of salgados (fried snacks) and discuss the merits of Corintheans over Palmeiras (both soccer teams from opposite sides of the city) with the locals.
If, on the other hand, you're flying into Congonhas, which is very much in the middle of the city, getting anywhere in Sao Paulo is easy and quick.