Mayorkas was appointed by President Biden in 2021 as the seventh United States Secretary of the Department of Homeland Security (DHS). He is the first refugee and first person born in Latin America to lead DHS.

During the Obama administration, Mayorkas was employed by the DHS, first as director of United States Citizenship and Immigration Services (2009–2013), and then as deputy secretary of DHS (2013–2016).

Mayorkas is Jewish and served as a board member for HIAS (Hebrew Immigrant Aid Society), a Jewish organization that facilitates immigration, during his time in office as the head of US Immigration.

Mayorkas implemented the Deferred Action for Childhood Arrivals (DACA) process in 2009 under the Obama regime. Mayorkas was also involved in the DHS counterterrorism and anti-cybercrime efforts, as well as its public-private partnerships, and efforts to fight antisemitism.

According to BNN Breaking news, the US government has been channeling millions of dollars to HIAS through the Office of Refugees Resettlement (ORR). The funds have been instrumental in facilitating the immigration of around 500,000 illegal immigrants from South America and Central America into the USA.

On February 13, 2024, Mayorkas was impeached, with a 214–213 vote, by the United States House of Representatives. Mayorkas is the second Cabinet member to have ever been impeached in US history, and the first Cabinet secretary to be impeached in almost 150 years.