The U.S. Sentencing Commission decided Friday that nearly 50,000 federal drug offenders currently in prison are eligible for reduced sentences, a move that could flood the nation’s courts and prosecutors with applications for leniency.

By a unanimous vote, the commission made retroactive an earlier change that had lightened potential punishments for most future drug offenders who are sentenced starting in November. Friday’s move extends that change to 46,000 current inmates, allowing them to have their cases reviewed again by a judge.

The action by the commission — an independent agency that sets sentencing policies for federal crimes — means that nearly half of the nation’s 100,000 federal drug inmates can apply for reductions. Those eligible could have their sentences shaved by an average of about two years, the commission said. Congress has until November to void the move, which would take effect next year, but there is little indication of opposition on Capitol Hill.

The sentencing commission vote is the latest sign of an emerging shift in the country’s approach to criminal justice, particularly illegal drugs, in which the prevailing tough-on-drugs mentality is giving way to an increased emphasis on treatment and health. Democrats and some Republicans have supported slicing sentences for federal drug crimes, while at least 30 states have modified drug-crime penalties since 2009.

Yet the issue remains highly emotional for many, with the sentencing commission receiving more than 60,000 letters before Friday’s vote, including from dozens of lawmakers, judges, attorneys and advocacy groups. The overwhelming majority favored the change, the commission said.

Advocates hailed the decision — which applies to most trafficking cases regardless of the drug — as among the most significant drug-law reforms in a generation, saying it will help reverse years of tough policies dating to the 1970s that have included controversial mandatory minium sentences for nonviolent drug offenders.

“Tens of thousands of prisoners stand to benefit from this very just and very bold decision, and of course tense of thousands of their loved ones,” said Mary Price, general counsel for Families Against Mandatory Minimums, an advocacy group. “It was a profound decision and a bold move by the commission, but also absolutely the right thing to do.”

But some federal prosecutors and judges expressed strong opposition, warning that dangerous criminals could be freed and that judicial caseloads could skyrocket, especially along the southwest border in Texas, where the highest numbers of prisoners will be eligible for sentencing reductions.

“We’re just disappointed,” Dennis Boyd, executive director of the National Association of Assistant U.S. Attorneys, said Friday. “We were hoping for something different.”

The organization, which represents prosecutors who will be forced to respond to petitions for lower sentences, had told the commission in a letter that “tough sentencing laws . . . led to safer communities, which are now threatened.”

Despite the dissension in the ranks, Friday’s change is a personal victory for Attorney General Eric H. Holder Jr., who has been at the forefront of efforts to reform the criminal justice system and has sought to eliminate mandatory minimum sentences for nonviolent drug crimes.

Given Holder’s focus on the issue, some reform advocates were surprised when his department last month embraced a tougher proposal that would have allowed only about 20,000 current inmates to apply for leniency. The Justice Department’s plan would have excluded inmates who were violent and had significant criminal histories.

A federal law enforcement official familiar with Holder’s views said the Justice Department proposal was an acknowledgment of the opposition from some prosecutors who did not want to reopen closed cases and worried that the courts would be overwhelmed.

“It was an attempt to form a compromise within the prosecutor community,’’ said the official, who spoke on the condition of anonymity to discuss internal deliberations.

In private discussions with Justice officials, the sentencing commission then proposed more than doubling the number of eligible inmates but delaying any reduced sentences until November 2015. In a phone call Thursday, Holder told Judge Patti B. Saris, who chairs the commission, that the department would endorse that plan.

Since judges can review leniency applications over the next year, the federal law enforcement official said the department “thought the year-long delay was an alternative way to resolve the public safety concerns because any individuals with violent criminal histories will be filtered out.’’

In a statement Friday, Holder said he is pleased with the outcome, calling it a “milestone” and saying that the Bureau of Prisons would immediately begin notifying eligible inmates that they can apply for reductions.

The sentencing commission — which consists of seven voting members appointed by the president and confirmed by the Senate — initially estimated that 51,000 offenders now imprisoned would be eligible. With the one-year delay, that number fell to 46,000 because some prisoners who might have been released right away will now have to serve another year.

Federal sentencing guidelines rely on a numeric system based on a number of factors, including the particular crime, whether a weapon was involved and a defendant’s criminal history. The change decreases the value attached to most drug-trafficking offenses — regardless of the type or amount of drug — and the commission estimates that offenders will be eligible for an average reduction of 25 months. Since 2005, federal judges have not been required to adhere to the guidelines, but they must still take them into account.