São Paulo is Brazil's largest city and cultural and culinary capital, while Brasília is the country's purpose-built political capital — a planned modernist city unlike anywhere else in South America.
Brasília's entire identity is architectural — Palácio da Alvorada, Palácio do Planalto, and the Congresso Nacional are all Oscar Niemeyer modernist landmarks, and the whole city is a UNESCO World Heritage Site for its planned design. São Paulo's architecture is denser and more organic, built up over more than a century rather than designed from scratch.
São Paulo is the clear cultural heavyweight — MASP (Museu de Arte de São Paulo) and the Pinacoteca do Estado make it Brazil's premier art city. Brasília's Museu Nacional da República, itself another striking Niemeyer building, is worthwhile but far smaller in scope.
São Paulo's Vila Madalena and Liberdade (its Japanese quarter) give it one of the most diverse food and nightlife scenes in South America. Brasília, designed around government function rather than street life, has far fewer walkable neighborhoods and a much quieter evening scene outside its ministries.
São Paulo is Brazil's main international gateway alongside Rio, with by far the most flights, hotels, and things to do. Brasília is a planned, spread-out city built for cars, with sights like Praça dos Três Poderes spaced far apart — genuinely interesting for a day or two, but not built for extended wandering.
Choose São Paulo for Brazil's best museums, food, and nightlife in one massive, walkable-in-parts city. Choose Brasília for a unique day or two seeing one of the 20th century's most ambitious planned cities. Most travelers treat Brasília as a short, deliberate detour rather than a primary Brazil destination.