"Thousands of special interest groups stand up for African-Americans, Mexican Americans, Jewish Americans, etc.," he said
in a YouTube video. "The fact is that European Americans need at least one man in the United States, one man in Congress, who will defend their rights and heritage."
Duke, a former Republican state representative and convicted felon, said his emphasis on the rights of European Americans is what distinguishes him.
"I believe in equal rights for all and respect for all Americans. However what makes me different is I also demand respect for the rights and the heritage of European Americans," he said.
Republican Sen. David Vitter announced last year
that he would not run for office again when his term was up at the end of this year.
"We must stop the massive immigration and ethnic cleansing of the people whose forefathers created America," Duke said in the message.
The former hate group leader said he popularized the "America First" slogan that Republican nominee Donald Trump has now embraced.
"I was the first major candidate in modern times to promote the term and policy of "America First." We can not have free trade without fair trade we must protect American jobs and businesses," said Duke, who also said he is "overjoyed" by Trump's campaign.
Duke, who previously praised Trump's candidacy, said he's "overjoyed" by Trump's campaign.
"The New York Times admitted that my platform became the GOP mainstream and propelled Republican control of Congress," he said. "I'm overjoyed to see Donald Trump and most Americans embrace most of the issues that I've championed for years. My slogan remains 'America First.'"
Trump disavowed Duke in March after failing to do so when asked about the hate group leader's support on CNN. The uproar started when Trump was asked by CNN's Jake Tapper on "State of the Union" if he would disavow Duke and other white supremacist groups supporting his campaign.
"Just so you understand, I don't know anything about David Duke, OK?" Trump responded. The next day, Trump blamed a "bad earpiece" during an appearance on NBC's "Today."
On Friday, Trump campaign spokeswoman Hope Hicks said Trump "has disavowed David Duke and will continue to do so."
The National Republican Senatorial Committee leadership said Friday that they will not back Duke's run "under any circumstance."
"Louisiana voters will be able to choose from several Republican Senate candidates who will have a great impact on the Bayou State and the future of our country. David Duke is not one of them," the group's executive director Ward Baker said in a statement. "He will not have the support of the NRSC under any circumstance."
And on Saturday, Republican National Committee Chairman Reince Priebus condemned Duke, tweeting, "David Duke & his hateful bigotry have no place in the Republican Party & the RNC will never support his candidacy under any circumstance."
Other Republicans running for the seat include Rep. John Fleming, Rep. Charles Boustany, Jr., Retired Colonel Rob Maness, former Rep. Joseph Cao, State Treasurer John Kennedy and Abhay Patel.
The Republican Party of Louisiana said Duke history of "hate" causes them to oppose his candidacy.
"David Duke's history of hate marks a dark stain on Louisiana's past and has no place in our current conversation," the group said in a statement. "The Republican Party of Louisiana will play an active role in opposing David Duke's candidacy."
CORRECTION: An earlier version of this story incorrectly described David Duke's political career. He was a state representative.