Nataniël le Roux launched his career in 1987 with the release of his first single, Maybe Time. Since then he has released fifteen studio- and two live- albums, staged more than eighty original theatre productions and published twenty-one books. In 1997 he also released a four-track EP entitled The Diva Divine with opera singer Mimi Coertse. His many theatre shows, often staged at the Johannesburg casino Emperor's Palace, have won him multiple awards.

Nataniël manages a company specialising in lifestyle goods called Kaalkop, which means "bald" in Afrikaans, but implies "honest" or "unpretentious".

After starring in the TV series Another Life With Nataniël (1998-1999) and Project Fame (2004), Nataniël created and hosted Die Nataniël Tafel, a cooking and entertainment program in five seasons (2012-2014), on the South African television channel kykNET. In 2014 he starred in the South African TV drama Almon, Henry which he also wrote.[9] In recent years he has created and hosted five seasons of his TV show Edik van Nantes (2015–2020) on the same channel alongside his brother, Erik le Roux.

During live musical performances, he is often accompanied on stage by Steinway pianist Charl du Plessis, or the Charl du Plessis Trio.

Nataniël has been a column writer for Sarie magazine since 2002, and has recently published the first part of his memoirs.