American mosque on Wednesday, offering a high-profile rebuttal of harsh Republican election-year rhetoric against Muslims.
Obama, whose grandfather converted to Islam, will make the short trip to the Islamic Society of Baltimore mosque, where he will meet community leaders and deliver remarks.
He has visited mosques in Malaysia, Indonesia and Egypt as president, but has yet to visit one of America's 2,000-plus places of Islamic worship.
In 2009, a freshly elected Obama traveled to Cairo to call for a "new beginning" with the Muslim world.
Much of Obama's foreign policy agenda has focused on improving ties with Muslim nations, from making a nuclear deal with Iran to ending wars in Iraq and Afghanistan.
But the effort has been stymied by continued confrontation with jihadist groups and military strikes in Afghanistan, Iraq, Libya, Pakistan, Somalia, Syria and Yemen.
His latest effort to ease interfaith relations comes as a shrill election debate has sullied America's image abroad and jihadist attacks in San Bernardino and Philadelphia threatened to shatter post-9/11 religious solidarity at home.
Six days after the 2001 attacks in New York and Washington, then president George W. Bush visited the Islamic Center of Washington, declaring "Islam is peace."
Today, Republican presidential candidate Donald Trump has wooed conservative voters by demanding a ban on Muslim immigrants, while frontrunner Ted Cruz has advocated Christian-only admissions and championed "Judeo-Christian values."
"We're seeing all this right wing anti-Muslim hate. It's the perfect time for him to come," said Riham Osman of the Muslim Public Affairs Council, an advocacy group.
– Law-abiding Americans –
The White House is keen to offer an image of America that stresses the country's secular tradition and contrasts with Republicans' "divisive rhetoric."
White House spokesman Josh Earnest said Obama will "affirm the important role that Muslim Americans play in our society" and argue that "law-abiding Americans should be able to worship God in the manner that they see fit."
"And they shouldn't be subject to ridicule or targeting by anybody, let alone somebody who aspires to leading the country," Earnest added.
"We have seen an alarming willingness on the part of some Republicans to try to marginalize law-abiding, patriotic Muslim Americans, and it is offensive."
Obama is also likely to restate his case that organizations like the Islamic State group pervert Islam and do not represent the vast majority of Muslims.
The United States is home to around 3.3 million Muslims.
Around 81 Muslim-Americans were involved in violent extremist plots in 2015, according to the Triangle Center on Terrorism and Homeland Security.
But Obama is expected to call on Muslim leaders to help tackle radicalization.
"We know that there are extremist organizations like ISIL that are seeking to use social media to radicalize vulnerable members of the population," said Earnest.
"Certainly the leaders in the Muslim community have a strong interest in preventing that from happening."
That does not sit so well with members of the Muslim community.
"I know national security will come up in the speech just because of the climate of today," said Osman. "I wish he wouldn't."
"It does upset me a little bit that it is his first time coming to visit a mosque, and there will be kids there who have grown up in this post 9/11 era and their faith is constantly linked to national security and extremism."