"This effort to basically marginalize and humiliate the attorney general is not going over well in the Senate," Graham told reporters today. "I don't think it's going over well in the conservative world ... If Jeff Sessions is fired, there will be holy hell to pay."
He added, "Any effort to go after [special counsel Robert] Mueller could be the beginning of the end of the Trump presidency, unless Mueller did something wrong."
Graham, a Senate Judiciary Committee member from South Carolina, stressed that there would be no confirmation hearing for a new attorney general in 2017 and that Trump should respect Sessions as a person who "deserves better."
He echoed Sen. Chuck Grassley, R-Iowa, who subtly critiqued Trump on Twitter on Wednesday evening, saying the Judiciary Committee is focusing for the rest of the year on judicial and sub-Cabinet nominees and would not consider an attorney general nominee.
Senators such as Graham and Grassley have backed Sessions as Trump jabbed him this week for being "weak" on the Hillary Clinton email investigation and for not firing acting FBI Director Andrew McCabe, who was closely tied to now-former FBI Director James Comey.
Sen. Orrin Hatch, R-Utah, told ABC News on Wednesday, "Well, I'm a little bit surprised at some of the reported comments. Jeff has been very loyal to the president, and I think that he deserves loyalty back ... so I hope that that will be reciprocated."
The Trump-Sessions tension ratcheted up July 19, when the president told The New York Times that he was disappointed that Sessions had recused himself from the Department of Justice's Russia investigation, leaving the power to appoint a special counsel to Deputy Attorney General Rod Rosenstein. Rosenstein appointed Mueller, who Trump said in the interview "should never have been appointed."
Graham reiterated his support for Mueller's Russia investigation, saying he has no reason to think Mueller is compromised. Graham warned that he will introduce a bill next week that would prevent the special counsel from being fired when "empaneled to investigate the president" unless there is judicial review of the firing.
"The idea that the president would fire Mueller or have somebody fire Mueller because he doesn't like Mueller or Mueller is doing something he doesn't like — then we have become Russia," Graham said. "So the red line should never be drawn ... No president can do that."
Graham added that the "president is not in the business of drawing red lines when it comes to the law" and that he hoped Trump would "calm down" to work with Congress on Afghanistan, taxes and health care instead.
When Rosenstein appointed Mueller on May 17, Trump took a defensive stance, saying a thorough investigation will confirm "no collusion" between his presidential campaign and Russia and that he wanted to "fight back." Mueller resigned from the law firm Wilmer Hale, which has among its clients Trump's son-in-law and adviser Jared Kushner — which Christopher Ruddy, a friend of Trump's, told "PBS Newshour" in June the president thought presented "conflicts."
But White House communications director Anthony Scaramucci told conservative radio host Hugh Hewitt on Tuesday morning that he asked Trump, "Why would you fire him?" and advised against pursuing it.
ABC News' Ali Rogin, Saisha Talwar and Dylan Wells contributed to this report.