Cyrus R. Vance Jr., the Manhattan district attorney, announced on Friday he would not run for re-election, setting off a wide-open race to lead one of the most important crime-fighting offices in the country and making it highly likely that any potential case against President Donald J. Trump will be left in a newcomer’s hands.

Mr. Vance made the long-expected announcement in a memo to his staff early Friday morning, just weeks before the filing deadline for the race. The many candidates clamoring to replace him are, with few exceptions, seeking to fundamentally reshape the office.

A scion of one of Manhattan’s well-known liberal families, Mr. Vance is one of only four people to be elected Manhattan district attorney in nearly 80 years. He took office in 2010 and presided over the office during a decade when crime numbers plummeted and attitudes toward the criminal justice system changed.

Mr. Vance was the handpicked successor of Robert M. Morgenthau, who served for 35 years and built the office’s reputation as one of the largest and most ambitious prosecutorial agencies in the country. When Mr. Vance took the helm, he vowed to stick to the practices that he said had served the office in good stead for years. He said while campaigning that he would not attempt to fix what was not broken.

But at times, Mr. Vance, 66, seemed to be swimming against the current of public opinion in his liberal district, as the Black Lives Matter and Me Too movements raised awareness of ingrained biases in the criminal justice system and led to calls for wholesale reform.

The eight-way race to succeed Mr. Vance reflects those newer political currents. Three of the candidates running to be New York County’s lead prosecutor have no prosecutorial experience at all. The five others in the race have distanced themselves from Mr. Vance, including two who worked in his office, Lucy Lang and Diana Florence, who rarely mention his tenure in a positive light.

Mr. Vance’s announcement, first reported in The New Yorker, was widely expected. He had not been actively raising money or campaigning.

During his three terms in office, Mr. Vance won praise for pioneering data-driven methods to more effectively target violent crime, but was faulted in some quarters for being too tentative when investigating powerful figures.

“He was cautious in what high-profile cases he brought,” said Marc F. Scholl, a veteran of the district attorney’s office who left for private practice in 2017. “He was more interested in not making mistakes than anything else.”

Mr. Vance’s critics have focused on his handling of sex crime investigations, starting with the case of Dominique Strauss-Kahn, the former head of the International Monetary Fund who was accused of sexually assaulting a hotel housekeeper in 2011. Mr. Vance dropped the charges against Mr. Strauss-Kahn after prosecutors in his office raised questions about the victim’s credibility.

After the case against Mr. Strauss-Kahn fell apart, Mr. Vance said that his success or failure could only be measured over time. Some of his most notable victories have involved the same figures whom critics said he had treated leniently earlier in his tenure.

For instance, in 2015, Mr. Vance chose not to press charges against the movie producer Harvey Weinstein, whom an Italian model had accused of groping her during an interview in his SoHo office. She later obtained an incriminating tape of him talking about the incident, but charges were dropped over prosecutors’ concerns a jury would not believe her.

But in 2018, the year after decades of allegations against Mr. Weinstein set off the Me Too Movement, Mr. Vance brought the first criminal charges against him. Mr. Vance won a major victory in February 2020 when Mr. Weinstein was found guilty of felony sex crimes against two women. The following month, he was sentenced to 23 years in prison.

Mr. Vance also drew fire, then praise, for his dealings with Mr. Trump.

After Mr. Trump rose to power, the district attorney was criticized for a 2012 decision to end a criminal investigation into fraud allegations against Mr. Trump and two of his children, Ivanka Trump and Donald Trump Jr.

Prosecutors had been looking into whether the Trumps misled investors in a condominium project. Mr. Vance said the investigation ended in part because victims would not cooperate after having reached a civil settlement with the Trump family.

For many Democrats, however, few of Mr. Vance’s triumphs loom larger than his dual wins at the Supreme Court as he later sought to investigate Mr. Trump and his business. Prosecutors are examining whether Mr. Trump fraudulently manipulated property values to obtain loans and tax benefits.

In July of last year, the justices declared that Mr. Vance’s office — and by extension, all state prosecutors — had the right to seek evidence from a sitting president in a criminal investigation, setting a lasting limit on the scope of presidents’ powers and immunity from prosecution.

And last month, the justices rejected in a brief unsigned order a last-ditch attempt to block Mr. Vance’s subpoena for Mr. Trump’s tax and financial records.

“I don’t know how many local prosecutors could do that,” said Karen Friedman Agnifilo, Mr. Vance’s longtime deputy. “Just the ability to bring that case, go to the Supreme Court and now to be in possession of Donald Trump’s tax returns and doing a sweeping criminal investigation into the former president of the United States.”

Mr. Vance was slower than some other big-city prosecutors when it came to certain reforms popular with progressives — Manhattan prosecutors were still taking on low-level marijuana cases as late as 2018 — but he did seek to reshape the office.

In response to crime dropping to lows not seen since the mid-20th century, his office cut total prosecutions by more than half and invited the Vera Institute of Justice, a nonprofit focused on criminal justice reform, to examine its record on racial disparities in prosecution.

He also poured money into community organizations that helped with crime prevention, and re-entry for those who had been incarcerated.

The funds came from the $800 million Mr. Vance obtained for the office through asset forfeiture — money reaped from settlements with big banks accused of violating federal sanctions. He used the windfall as seed money to fund various programs.

Perhaps the most expansive use of that money was its funding of a program to eliminate the nationwide backlog of rape kits — which preserve DNA evidence left by an assailant — in more than a dozen states. The push to clear that backlog has led to hundreds of prosecutions in unsolved cases and more than 100 convictions.

Mr. Vance also put to rest an older case that had haunted the city for decades. In 2017, a jury convicted a former bodega worker of killing Etan Patz, a boy who disappeared in SoHo on his way to school in 1979, changing the way many American parents thought about protecting their children.

The campaign to replace Mr. Vance has been dominated by talk of deep changes to the criminal justice system. Two of the candidates, Tahanie Aboushi and Eliza Orlins, have vowed to reduce the size of the Manhattan district attorney’s office, currently the largest local prosecutor’s office in the country, by 50 percent or more in order to limit its power.

One potential strike against those candidates — as well as Dan Quart, a state assemblyman — is their lack of prosecutorial experience, which each has touted as a virtue. When it comes to a possible case against Mr. Trump, veterans of the office have argued, there is little substitute for having handled complicated investigations and high-pressure prosecutions.

But some progressive Democrats say that the candidacies of Ms. Aboushi, Ms. Orlins and Mr. Quart reflect a hunger for changes in how prosecutors handle cases in Manhattan that acknowledge the harm the system has done to Black people and other marginalized communities.

Janos Marton, a leader in New York’s movement to reduce incarceration, was a candidate to replace Mr. Vance until he dropped out of the race in December. He said Mr. Vance and his assistants, despite having tried at times, had not kept pace with reforms prosecutors were adopting elsewhere, like in Philadelphia, Chicago and even Brooklyn.

“They enacted really punitive policies against low-income communities of color and even the reforms that they occasionally would embrace were quite far behind the curve,” he said.

The investigation into the Trump organization is ongoing. Last month, The New York Times reported that Mr. Vance had enlisted a former federal prosecutor with expertise in organized crime and white collar crime to help with the inquiry. If it results in charges, Mr. Vance’s successor will almost certainly oversee the case.

Mr. Vance’s announcement will inevitably prompt considerations of his legacy. But if he does bring charges against Mr. Trump, that action, and the success or failure of the resulting case, may single-handedly determine how Mr. Vance is remembered.