It "is a murky area," Obama told the magazine, "where you have large-scale, commercial operations that may supply medical marijuana users, but in some cases may also be supplying recreational users. In that situation, we put the Justice Department in a very difficult place if we're telling them, 'This is supposed to be against the law, but we want you to turn the other way.' That's not something we're going to do."
Obama and the Office of National Drug Control Policy say the negative impacts of widespread marijuana legalization loom large.
Legalization would lower the price of "weed," thereby fueling its use and triggering more widespread negative health effects and subsequent costs of care, the administration says in its official policy position. Officials also say legalization would do little to curb drug violence or eliminate cartels.
"When you're talking about drug kingpins, folks involved in violence, people who are peddling hard drugs to our kids and our neighborhoods that are devastated, there is no doubt we need to go after those folks hard," said Obama.
"It makes sense for us to look at how we can make sure that our kids are discouraged from using drugs and engaging in substance abuse generally," he said. "There's more work we can do on the public health side and the treatment side."
Colorado and Washington are the first states to legalize recreational use of marijuana, presenting a fresh challenge for the Obama Justice Department to navigate in a second term.
While public opinion has shifted toward legalization over the past few years, Americans remain divided about the personal use of pot.
Fifty percent of American adults oppose legalizing the possession of small amounts of marijuana for personal use, while 48 percent would support such a measure, according to a November ABC News/Washington Post poll. The survey has a margin of error of plus or minus 3.5 points.
Colorado Gov. John Hickenlooper, a Democrat who personally opposed legalization, on Monday formally approved the voter-backed amendment to the state constitution legalizing recreational use of marijuana.
The measure will allow individuals to possess one ounce of pot and up to six marijuana plants and licensed stores to sell marijuana starting next year.
Washington State last week officially became the first to allow recreational use of marijuana when a voter-approved ballot measure took effect.
In both states, pot use remains illegal in public. Eighteen states have approved the use of marijuana for medicinal use with a doctor's order. Federal law still prohibits all use and sale of marijuana.
ABC News' Jason Ryan contributed to this report.