McCain suggested that the comments by the Georgia Democrat and veteran of the civil rights movement carry more weight than those of a Virginia Republican Party leader who compared Democratic rivalto Sept. 11 mastermind Osama bin Laden.
"This is not just some obscure party official," McCain said in an interview aired by CNN. "And that's what's so totally unacceptable about it."
According to Time magazine, Virginia Republican Party Chairman Jeffrey M. Frederick recently told McCain volunteers in the state that Obama and bin Laden "both have friends that bombed the Pentagon."
McCain has repudiated similar past statements about Obama, but did not specifically address Frederick's comments in the interview.
"You have people in political campaigns on the outer most fringe on both ends of the spectrum," McCain said.
McCain and running mate Sarah Palin have said Obama failed to tell the truth about his relationship with 1960s radical William Ayers, and Palin has accused Obama of "palling around with terrorists," meaning Ayers.
Ayers was a founder of the Weather Underground, a radical, Vietnam War-era group that claimed responsibility for a series of bombings, including nonfatal explosions at the Pentagon and U.S. Capitol.
Ayers also hosted a reception for Obama in 1995, when Obama was beginning his political career. The two also have worked with the same nonprofit organizations in Chicago. McCain's campaign has tried to exploit those ties, even while saying it disagreed with Frederick.
"While Barack Obama is associated with domestic terrorist William Ayers, the McCain campaign disagrees with the comparison that Jeff Frederick made and believes that his comment was not appropriate," said McCain-Palin spokeswoman Gail Gitcho.
In a statement Saturday, Lewis said McCain and Palin were "sowing the seeds of hatred and division" and "hostility in our political discourse," and noted the tone that segregationist Gov. George Wallace fostered in 1960s Alabama.
"George Wallace never threw a bomb. He never fired a gun, but he created the climate and the conditions that encouraged vicious attacks against innocent Americans who were simply trying to exercise their constitutional rights," said Lewis, who is black. "Because of this atmosphere of hate, four little girls were killed on Sunday morning when a church was bombed in Birmingham, Alabama."
Obama's campaign said he doesn't believe McCain or his policy criticism is comparable to Wallace and his segregationist policies.
Lewis issued a follow-up statement Saturday, saying it was not his "intention or desire" to directly compare McCain or Palin to Wallace.
Lewis' comments followed reported examples of anger at McCain-Palin rallies that has been aimed at Obama, the first black man to be a major party's nominee for president. GOP supporters have shouted "traitor," "terrorist," "treason," "liar" and "off with his head."
McCain defended his audiences, saying most who attend the rallies are "good and decent and patriotic Americans."
"To somehow intimate that the overwhelming majority of those people, with rare exception, are somehow not good Americans or are motivated by anything but the most patriotic motives is insulting and I won't accept that insult," he said.
Several times on the campaign trail this year, McCain has praised Lewis, invoking the Congressman's name in connection with Dr. Martin Luther King and telling the civil rights veteran's story during an event in Selma, Ala.
During the primary campaigns, on Martin Luther King Day, CBS News asked all the candidates to. McCain noted that he was in a prison camp in Vietnam when King was assassinated, but referenced Lewis.
"I did not know Dr King," McCain said. "But I know John Lewis, and I know what he represents. And John Lewis and I may disagree on some issues, but that's the kind of person I think are true American heroes."
In April, while in Selma, Ala. -- the backdrop for a milestone civil rights march on March 7, 1965 -- McCain, who suffered a fractured skull from a beating during the protest.
In August, while appearing at a forum on faith, McCain was asked to name three "wise people" he would listen to. He cited Lewis as well as Gen. David Petreaus, head of U.S. troops in Iraq, and former eBay CEO Meg Whitman, a top adviser to his campaign.