In an explosive BBC interview, Aisha Buhari said the president "does not know" the true character of most of the top officials he has appointed into government.
Aisha Buhari cried out that the government had been hijacked, saying a "few people" were behind the presidential appointments, sidelining those who worked hard to make him President.
Buhari was elected last year with a promise to tackle corruption and nepotism in government.
His wife's decision to go public with her concerns will shock many people, but it shows the level of discontent with the president's leadership, says the BBC's Naziru Mikailu in Abuja.
Buhari famously remarked at his inauguration that he "belongs to nobody and belongs to everybody."
In the interview with Naziru Mikailu, Aisha said: "The president does not know 45 out of 50, for example, of the people he appointed and I don't know them either, despite being his wife of 27 years."
She said people who did not share the vision of the ruling APC were appointed to top posts because of the influence a "few people" wield.
"Some people are sitting down in their homes folding their arms only for them to be called to come and head an agency or a ministerial position."
Asked to name those who had hijacked the government, she refused, saying: "You will know them if you watch television."
On whether the president was in charge, she said: "That is left for the people to decide."
Mrs Buhari said her husband had not told her whether he would contest the 2019 election. "He is yet to tell me but I have decided as his wife, that if things continue like this up to 2019, I will not go out and campaign again and ask any woman to vote like I did before. I will never do it again."
Asked what she regarded as the government's major achievement, she said it was to improve security in the north-east where militant Islamist group Boko Haram has waged an insurgency since 2009.
"No-one is complaining about being attacked in their own homes. Thankfully everyone can walk around freely, go to places of worship, etc. Even kids in Maiduguri have returned to schools," Mrs Buhari said, referring to the city which was once the headquarters of the terrorists.