She appears on Nicaraguan television almost every day.
Critics accuse the first couple of running Nicaragua - which has elections in November - like a personal fiefdom.
While President Ortega rarely speaks to the media, his wife is regularly seen on TV discussing policy and promoting her own brand of New Age spirituality.
Mother of the president's seven children, she is fluent in English and French in addition to being a renowned poet.
She also has a reputation for wearing colourfully extravagant outfits and jewellery more commonly seen in the hippy 1960s.
Correspondents say many Nicaraguans see Ms Murillo as wielding the most power in her country because of her higher public profile.
Husband and wife officially submitted their candidacy papers in the capital Managua, accompanied by the legal adviser of their Sandinista party.
Hundreds of Sandinista supporters cheered the couple when they left the building.
But opposition supporters are concerned her promotion may herald the rise of a new family dynasty in the impoverished Central American nation.
Mr Ortega, 70, is a former left-wing guerrilla who formed part of the government junta following the Sandinista revolution against the dictatorship of the Somoza family, which ruled Nicaragua for four decades.
The Cuban-inspired Sandinistas seized power in 1979.
The party lost elections in the 1990s, but Mr Ortega returned to power in January 2007, after a successful election campaign.
Courtesy: BBC News
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