Flake, a Republican up for re-election next year, defended his potential Democratic challenger Deedra Abboud on Twitter after she posted a message on her campaign page on Facebook with an image of the US Constitution.
Abboud's post: "Almost 250 years ago a group of dreamers came together and sketched out a revolutionary vision. No longer would they be shackled to the whims of a distant government, nor bound to the religion of an idiosyncratic king. They set out to forge their own futures, determine their own destinies, and follow their own faith.
"In their infinite wisdom, the Founding Fathers decreed that this nation would separate church and state, and in doing so protect both institutions. Government would be free from religious overreach, and religion would be free from government interference."
Trolls responded with vitriol focused on her religion, with one user writing: "Sorry no room for Muslims in our government. Nice try though you are quoting the Muslim brotherhood."
Another user responded, "Nice try but your first love is Satan (AKA Allah) and your second love is to a litter box your 'people' come from. You are as American as Chinese checkers."
And another simply wrote "F*#k you Muslim b*#%h."
Flake expressed support for Abboud on Twitter on Tuesday night, encouraging her not to be swayed by the negativity.
"Hang in there @deedra2018. Sorry you have to put up with this. Lots of wonderful people across AZ. You'll find them."
Abboud, a Phoenix attorney and founder of a leadership consulting firm, thanked the man whose job she's seeking.
"Thank you @JeffFlake for leadership in rejecting behavior that doesn't reflect our American values. AZ's amazing people deserve more of this."
Abboud told CNN that she received similar negative comments about her religion on social media when she announced her campaign in April, but they had tapered off after the first two weeks.
"We have to step forward because this is America. This is the United States of America -- there is a promise here," she said. "There is a promise that every person has equal opportunity."
Abboud, a native of Little Rock, Arkansas, is running in the August 2018 Democratic primary for the seat. The general election follows that fall.
Flake has called out the mistreatment of Muslims before. After President Donald Trump's executive order in January appeared to target Muslims broadly, the Republican told CNN:
"President Trump and his administration are right to be concerned about national security, but it's unacceptable when even legal permanent residents are being detained or turned away at airports and ports of entry," the senator said in a statement. "Enhancing long term national security requires that we have a clear-eyed view of radical Islamic terrorism without ascribing radical Islamic terrorist views to all Muslims."