Harkin said he didn't "like the smell" of a sex scandal that "cast a bad image on the Senate," Politico reported Monday.
"If it is true that indeed he did make ... payoffs and all that kind of stuff, then I would think the honorable thing would be to resign," Harkin said in an interview with the Washington publication.
Harkin's statement came as other Senate colleagues were considering whether to conduct public hearings into Ensign's extramarital affair with a former staffer.
The bipartisan Senate Ethics Committee hasn't ruled out a public hearing, which some insiders said could help force Ensign out of office. Several senators indicated to Politico they'd support seeing Ensign appear in a public forum to address the allegations.
Ensign admitted to having a nine-month affair in 2007-2008 with Cynthia Hampton, a former campaign aide married to Doug Hampton, a top staffer in the senator's office. The senator also revealed his parents paid the Hamptons $96,000 as they were leaving his office, which raised questions about whether it was a severance package that had to be reported under federal law.
Ensign denied violating federal laws or Senate rules and said he would participate in the investigations.