Emphasizing the need to upgrade infrastructure, modernize the tax system and labor laws, integrate with the U.S. economy, and allow private investment in the energy sector, Vicente Fox Quesada, the candidate of the National Action Party (PAN), was elected the 69th president of Mexico on 2 July 2000, ending PRI's 71-year-long control of the office.

As president, Fox continued the neoliberal economic policies that his predecessors from the PRI had adopted since the 1980s. The first half of his administration saw a further shift of the federal government to the right, strong relations with the United States and George W. Bush, unsuccessful attempts to introduce a value-added tax to medicines and to build an airport in Texcoco, and a diplomatic conflict with Cuban leader Fidel Castro. The murder of human rights lawyer Digna Ochoa in 2001 called into question the Fox administration's commitment to breaking with the authoritarian past of the PRI era. The Fox administration also became embroiled with diplomatic conflicts with Venezuela and Bolivia after supporting the creation of the Free Trade Area of the Americas, which was opposed by those two countries. His last year in office oversaw the controversial 2006 elections, where the PAN candidate Felipe Calderón was declared winner by a narrow margin over López Obrador, who claimed the elections had been fraudulent and refused to recognize the results, calling for protests across the country. In the same year, civil unrest in Oaxaca, where a teacher's strike culminated into protests and violent clashes asking for the resignation of governor Ulises Ruiz Ortiz, and in the State of Mexico during the San Salvador Atenco riots, where the State and Federal governments were later found guilty by the Inter-American Court of Human Rights of human rights violations during the violent repression. On the other hand, Fox was credited with maintaining economic growth during his administration, and reducing the poverty rate from 43.7% in 2000 to 35.6% in 2006.