Her announcement ended months of conjecture about whether Democrats could deliver a top-drawer challenger for targeted, off-year race, Roll Call reported.
"I have met with my supporters, we have had a great conversation, and determined and decided that we can next make the best move, the best difference in the commonwealth of Kentucky, by running for the U.S. Senate," Grimes said at an event in Kentucky.
National Democrats put all of the election hope with Grime after actress Ashley Judd announced in March she wouldn't run against McConnell.
A top fundraiser and hard-nosed campaigner, McConnell is a top target for Democrats in the 2014 cycle.
A Republican super PAC already started running advertisements attacking Grimes, linking her to President Obama, deeply unpopular in Kentucky, Roll Call said.
Grimes said she's not concerned about her underdog roll.
"I agree with thousands of Kentuckians that Kentucky is tired of 28 years of obstruction; that Kentucky is tired of someone who has voted against raising the minimum wage while all the while quadrupling his own net worth. Kentucky is tired of a senior senator that has lost touch with Kentucky issues, voters and their values," Grimes said during her announcement.