Hernández was born in Gracias, Honduras to Juan Hernández Villanueva and Elvira Alvarado Castillo, as the fifteenth of seventeen children. His siblings include Hilda Hernández (1966–2017) and Juan Antonio (Tony) Hernández, a former deputy now in U.S. federal custody on drug trafficking charges. He has a master’s degree in public administration from the State University of New York at Albany. On 3 February 1990, he married Ana García Carías. This union has produced three children: Juan Orlando, Ana Daniela, and Isabela. He was a coffee grower campesino in his native Gracias. He gained notoriety in Honduras when Liberal leader

Juan Orlando Hernández, who represented Lempira Department since 2001, was elected head of a National Congress where the National Party had a comfortable majority, on 21 January 2010, and took office four days later.

In 2012, he fought a campaign against Ricardo Álvarez to try to become the nationalist presidential candidate for 2013, and won the internal election of November 2012; Álvarez publicly denounced the result as fraudulent and demanded a “vote by vote” recount, which the Tribunal Supremo Electoral (TSE) rejected.

A poll conducted in May 2013 saw him in third place with a projected 18% of the vote. He began his presidential campaign in July 2013 in Intibucá and La Paz with a campaign entitled El Pueblo Propone (The People Propose in English). He campaigned for the military to police the streets, and claimed that his closest rival Xiomara Castro wanted to remove the Policía Militar (English: Military Police) which were already in Honduras’ two main cities. He won the election, beating Castro by 250,000 votes.

Orlando Hernández was identified as a co-conspirator in a drug trafficking and money laundering case against his brother, according to document filed in U.S. district court. Prosecutors say $1.5 million in drug proceeds was used to help elect him in 2013. Hernández responded saying he is foe of traffickers who are out for revenge against him.

On 22 April 2015, the Supreme Court unanimously allowed presidential re-election. On 12 March 2017, Hernández became the National Party candidate by defeating his rival Roberto Castillo during the National Party primary. The Honduran Constitution allows revocation of citizenship of anyone who promotes changing the law to allow re-election, however Hernández’s National Party, which also controls Congress, says a Supreme Court ruling last year allows him to stand for a new term. Opposition Liberal Party claims that the court does not have the power to make such decisions.

Hondurans both in and outside Honduras have protested against corruption in Honduras, allegedly by Hernández government as well as the judiciary, the military, the police and other public administration entities, demanding an end to what they say is the theft of funds and public money; for example, the embezzlement of the IHSS. In May 2015, Radio Globo discovered documents that allegedly showed that the Honduran National Party had received large amounts of cash from nonexistent companies through fraudulent contracts awarded by the IHSS when it was run by Mario Zelaya. The contracts were approved by congress when Hernández was its president and the party funding committee was headed by his sister, Hilda Hernández. Hernández has accepted that his election campaign received money from companies tied to the scandal, but denies any personal knowledge. By June 2015, Hernández had appointed a commission to investigate the cause of the corruption.

On 7 October 2015, the United States Department of Justice released a statement saying that Jaime Rosenthal, his son Yani Rosenthal and nephew Yankel Rosenthal, as well as seven other businesses, were labeled “specially designated narcotics traffickers” under the Foreign Narcotics Kingpin Designation Act, the first time this had been used against a bank outside the United States. As a result, the Honduran National Commission for Banks and Insurance (Comisión Nacional de Banca y Seguros, CNBS), forcibly liquidated the Banco Continental, property of the Rosenthal family, which was closed as of Monday, 12 October 2015, as well as other businesses and properties allegedly involved in money laundering. Hernández said that the financial system “is solid” and made it clear that this “is a problem between Banco Continental and the USA justice system”.

The US Central Intelligence Agency listed Hilda Hernández as Minister of Communications & Government Strategy. When questioned by journalist Fernando del Rincón of CNN en Español over the appointment of his sister, Juan Orlando Hernández said that his sister did not hold any position of Secretary of State (but rather, “Advising Minister”) and did not manage a budget. As corruption enquiries continued, on 2 January 2016 Hilda Hernández left her position in the government.

In 2017, the Drug Enforcement Agency in Miami arrested Hernández’s brother, Juan Antonio Hernández, for drug trafficking and for using Honduran military personnel and equipment to ship cocaine to the United States on behalf of the Mexican Sinaloa Cartel.

The President was re-elected in 2018 after a vote deemed fraudulent by the opposition and international observers. The government declares a state of emergency. Some 30 demonstrators were killed and more than 800 arrested. According to the United Nations and the Inter-American Commission on Human Rights, “many of them were transferred to military installations, where they were brutally beaten, insulted and sometimes tortured”.

On 21 June 2018, president Hernández ordered units of the Honduran army and the military police in the streets of the capital after renewed protests. According to a es:Hospital Escuela Universitario spokesperson, at least 17 people suffered bullet wounds as a result of violence in the protests, and two of them died at the hospital.

In April 2019, new anti-privatisation and anti-corruption protests erupted, lead by Tegucigalpa Autonomous University students and by health care workers. Tear gas was used against the protesters in demonstrations that took place in the center of Tegucigalpa.

After Tony Hernández’s conviction on October 18, 2019, 7,000 supporters of President Juan Orlando Hernández, including members of the official National Party of Honduras, marched in Tegucigalpa. President Hernández criticized his brother’s conviction as basado en testimonios de asesinos (“based on testimony from killers”) and denied that Honduras has become a narco-state.

On 17 June 2020, President Orlando Hernández and his wife, Ana García, reported that they had been infected by COVID-19. Orlando Hernández had instituted tough measures to prevent the spread of the disease, including enforced social distancing, the use of face masks, and a curfew.