The poll commissioned by the St. Louis Post-Dispatch/KMOV-TV shows Obama leading the race with 68 percent to Keyes' 23 percent. Nine percent were undecided.
Officials at the firm that conducted the poll say they can't remember the last time there was a gap like that between two newcomers.
Obama is an Illinois state senator from Chicago. Keyes is a conservative political commentator and two-time presidential candidate from Maryland.
They are competing for the seat now held by Republican U.S. Sen. Peter Fitzgerald, who decided not to seek a second term.