Kulsoom Nawaz will contest the seat her husband was forced to vacate last month after becoming embroiled in the Panama papers scandal.
Mr Sharif resigned after the papers revealed his children were linked to offshore companies that owned properties in London.
He has consistently denied any wrongdoing.
But Pakistan's Supreme Court disqualified him from office after ruling Mr Sharif had been dishonest in not disclosing his earnings from a Dubai-based company in his nomination papers during the 2013 general election.
Kulsoom Nawaz's nomination papers for her husband's former constituency in Lahore were filed by the Pakistan Muslim League-Nawaz party.
She has never run for office before - but the party is hoping she will win "a big majority" in the by-election, which will take place in about 45 days.
This appears to be a change of plan for the family, who indicated originally that Mr Sharif's younger brother would run for the seat, and then the premiership.
But last week, the ruling party elected Sharif loyalist Shahid Khaqan Abbasi as prime minister.
It has been suggested he will hold office until elections next year.
The wife of Pakistan's ousted Prime Minister Nawaz Sharif has announced she is running for his parliamentary seat.