Calderón's presidency was marked by his declaration of war against the country's drug cartels only ten days after taking office; this was considered by most observers as a strategy to gain popular legitimacy after the convoluted elections. Calderón sanctioned Operation Michoacán, the first large-scale deployment of federal troops against the drug cartels. By the end of his administration, the official number of deaths related to the drug war was at least 60,000. The murder rate skyrocketed during his presidency parallel to the beginning of the drug war, peaking in 2010 and decreasing during his last two years in office. The main architect of the drug war, Genaro García Luna, who served as Secretary of Public Security during Calderón's presidency, was arrested in the United States in 2019 due to alleged links with the Sinaloa Cartel.

Calderón's term was also marked by the Great Recession. As a result of a countercyclical package passed in 2009, the national debt increased from 22.2% to 35% of GDP by December 2012. The poverty rate increased from 43 to 46%. Other significant events during Calderón's presidency include the 2007 establishment of ProMéxico, a public trust fund that promotes Mexico's interests in international trade and investment, the 2008 passing of criminal justice reforms (fully implemented in 2016), the 2009 swine flu pandemic, the 2010 establishment of the Agencia Espacial Mexicana, the 2011 founding of the Pacific Alliance and the achievement of universal healthcare through Seguro Popular (passed under the Fox administration) in 2012. Under the Calderón administration sixteen new Protected Natural Areas were created.