Machado began her political career as a founder of the vote-monitoring organization Súmate. She is the National Coordinator of the political party Vente Venezuela and ran in the 2012 opposition presidential primary, which she lost to Henrique Capriles. During the 2014 Venezuelan protests, she played a leading role in organizing demonstrations against the government of President Nicolás Maduro.

In 2023, Machado won the opposition primary to become the unity candidate for the 2024 presidential election.The Venezuelan government subsequently barred her from running in the election. She named Corina Yoris as a replacement candidate, who was later replaced by Edmundo González Urrutia. The election results indicate that the opposition won the election, but the Maduro regime claimed victory. Shortly thereafter, in August 2024, Machado announced that she had gone into hiding, citing fears for her life and freedom under the authoritarian Maduro regime....

Domestically, Machado has called for the banning of reelection to political office, is in favor of same-sex marriage, supports the legalization of medical cannabis, and has called on a national debate regarding the legality of abortion [which is currently illegal in Venezuela]....

Machado was awarded the 2024 Václav Havel Human Rights Prize by the Council of Europe. She was one of three finalists along with Akif Gurbanov and Babutsa Pataraia. Along with Edmundo González, she was awarded the Sakharov Prize by the European Parliament on 24 October 2024 for "representing the people of Venezuela fighting to restore freedom and democracy."

This recognition of the struggle of all Venezuelans is a boost to conclude our task: to conquer Freedom.

We are on the threshold of victory and today, more than ever, we count on President Trump, the people of the United States, the peoples of Latin America, and the democratic nations of the world as our principal allies to achieve Freedom and democracy.

I dedicate this prize to the suffering people of Venezuela and to President Trump for his decisive support of our cause!