Olá, @anthonylomangino! If you mean “What’s up?” as in a casual greeting, the most common equivalents in Portuguese would probably be “Tudo bem?”, “Estás bom?” (when talking to men) or “Estás boa?” (when talking to women).
If you mean “What’s up?” as an expression of concern (like “What’s the matter? What’s wrong?”), the most common Portuguese equivalent would probably be “O que se passa?”/“O que é que se passa?”.