In a speech from Iowa, Pence made clear what he saw as those differences, particularly around Jan. 6 -- and why, in his view, they made Trump ineligible to ever serve in the White House again. Beyond his rebuke of the former president, Pence sought to stress his own conservative bona fides, including his longtime support of abortion restrictions, religious liberty principles and shrinking the federal government.
"I know we can bring this country back. We can defend our nation and secure our border. We can revive our economy. We can put our nation back on a path to a balanced budget," Pence said in a speech in Des Moines along family and supporters. His wife, former second lady Karen Pence, introduced him. He plans to barnstorm the early-voting state to beat Trump on the road to the Republican presidential nomination.
"We can defend our liberties and give America a new beginning for life. But it will require new leadership -- in the White House and the Republican Party," the former vice president said.
"Ours will be a vision grounded in freedom," he said, adding, "In all this work, we will not seek to divide the American people but instead appeal to the better angels of their nature."
In any other campaign cycle or with another pair of former U.S. leaders, Pence challenging Trump would likely have been a spectacle -- a media circus, even -- given how unusual it is for a former vice president to run against his ticket mate.
Instead, Pence's campaign debuted with a much quieter display and an appeal for a return to conservatism's roots. He chose to set his speech at a nondescript event space at a Des Moines community college, with a few hundred attendees gathered for remarks that also included some of the sharpest criticism yet that Pence has thrown at other candidates, including Trump.
"It would be easy to stay on the sidelines. But that's not how I was raised. I have longed believed to who much is given much will be required," Pence said. "That is why today before God and my family I am announcing I am running for president of the United States of America."
That echoed an announcement video Pence released earlier Wednesday in which he said, "Today, our party and our country need a leader that will appeal, as [Abraham] Lincoln said, to the better angels of our nature." In the video, Pence did not once mention or show an image of Trump or the event which caused their split: the Jan. 6 attack on the U.S. Capitol by a pro-Trump mob.
Instead, Pence cast the contest as a battle for a country that is "in trouble" under President Joe Biden and what Pence calls the radical left.
"I don't have to tell any of you here: This country is in a lot of trouble," he said in his kickoff speech.
While he touted his time serving in the Trump administration -- "together we cut taxes, destroyed ISIS, stood by our allies, stood up to our foes" -- he also again sought to stress his differences with Trump over Jan. 6, repeating his criticism that Trump's push to have him overturn their election loss "endangered my family and everyone at the Capitol."
"The American people deserve to know that on that day, President Trump also demanded that I choose between him and the Constitution. Now, voters will be faced with the same choice. I chose the Constitution and I always will," Pence said, later noting how his son, a Marine, has sometimes reminded him they both made the same pledge as public servants.
Without naming Trump specifically, Pence said that "anyone that puts themselves over the Constitution should never be president of the United States. And anyone who asked someone else to put them over the Constitution should never be president of the United States again."
Still, he said, "I understand the disappointment that many still feel about the outcome of the 2020 election."
But "elections are about the future," he said. And their differences in "vision," he suggested, led to his historically unusual decision to challenge the former president in 2024.
"Given our record, it might be fair to ask why I am challenging my former running mate? But let me say with my heart, it begins with a promise I made to the American people and to almighty God … and ends with different visions for the future," he said.
"My differences with my former running mate and others who are in this field also have to do with the values and policies upon which we have built this movement," he said.
And "when Donald Trump ran for president in 2016, he promised to govern as a conservative -- together we did just that. Today, he makes no such promise."
Pence also argued that Trump has been retreating from his support for abortion restrictions, treating the issue as an "inconvenience," and has no plan to address the country's long-term debt and spending issues.
The former congressman and Indiana governor filed paperwork on Monday with the Federal Election Commission to make his candidacy official.
Pence was a loyal No. 2 to Trump until Jan. 6, 2021 -- the climax to Trump's campaign to try and pressure Pence to reject their Electoral College loss, which Pence was constitutionally unable to do as vice president.
Later, Pence said he hoped Trump "would come around in time, that he would see the cadre of legal advisers that he surrounded himself with led him astray, but he hasn't done so."
Still, Pence said, "I have often prayed for him over the past few years, and I prayed for him again today."
While Trump has since repeatedly criticized Pence, some others have argued the former vice president should take on Trump to a greater extent.
For example, whereas fellow presidential candidate Asa Hutchinson condemned Trump following Trump's indictment by a New York grand jury -- on charges Trump denies -- Pence sounded similar complaints as the GOP's MAGA wing to try and delegitimize the case. He discouraged the protests the former president called for but noted their First Amendment right to peacefully assemble.
"Pence is very methodical and strategic," said Doug Heye, a former communications director for the Republican National Committee. "He's going to take Trump head-on on those things where, politically, he sees the best advantage -- and with an eye to history, as he's obviously trying to do."
Others, like GOP donor Dan Eberhart, who is backing Florida Gov. Ron DeSantis in the race, compliment Pence but are concerned with his level of support.
"Mike Pence is a true conservative and a great public servant. He just doesn't have the support among Republicans that he needs to be competitive. His net favorables with Republicans are 18%. That's comparable to Dan Quayle when he ran for president," Eberhart said.
However, Heye said it would be premature for anyone to count Pence out.
"That's why you see so many people getting in," Heye said. "They see a vulnerability with Trump, very clearly. And while he'll certainly have some obstacles, it's clear that Pence knows his weaknesses better than anyone else."
Pence is expected to court the evangelical vote, a significant block of Iowans, and campaign on Ronald Reagan-era conservative values. In his launch ad, he showed a photo of himself as a congressman in the Oval Office with Reagan.
Setting the groundwork for a campaign, Pence has already visited Iowa at least eight times this year, and allies launched a super PAC, called "Committed to America," in May. He also published a memoir, "So Help Me God," in November.
"It's hard to think of anybody who would have more credibility in that community than Mike Pence," said Heye.
Expanding primary field
Pence is not the only Trump loyalist-turned-challenger jumping into the 2024 race this week.
Former adviser and former ABC News contributor Chris Christie launched his campaign on Tuesday in New Hampshire, another pivotal early-voting state.
Pence joins a crowded primary field -- where early polls show Trump is ahead of his competitors right now.
Thus far, Pence and Trump's major GOP primary challengers are: Christie, DeSantis, Nikki Haley, Hutchinson, Vivek Ramaswamy and Tim Scott.