The warning from North Korea's Foreign Ministry was carried by the official Korean Central News Agency on Saturday.
It came hours after the U.N. Security Council approved tough new sanctions on the North to punish it for its latest nuclear test on May 25.
It did not elaborate if the blockade refers to an attempt to stop its ships or impose sanctions.
"North Korea's defiant reaction was predictable, and, in the past, additional sanctions follow North Korean nuclear or missile tests and, eventually, a new round of negotiations" said CBS News foreign Affairs Analyst Pamela Falk, "but the pattern has become increasingly volatile as Pyongyang increases the number of tests and moves closer to weaponizing its plutonium."
Through its statement, North Korea's Foreign Ministry acknowledged for the first time that the country has a uranium enrichment program, and insisted it will never abandon its nuclear ambitions. Uranium and plutonium can be used to make atomic bombs.
The sanctions are "yet another vile product of the U.S.-led offensive of international pressure aimed at undermining ... disarming DPRK and suffocating its economy," said the statement, issued by the state Korean Central News Agency.
It said the country's "development of uranium enrichment technology to guarantee nuclear fuel for its light-water nuclear reactor has been successfully going on and has entered a trial stage."
Until now, North Korea had denied the existence of a uranium enrichment program.
It was not clear if the statement was another attempt by North Korea at brinkmanship or if it was actually willing to engage in no-holds barred conflict. But it opened up the possibility that North Korea could develop nuclear weapons through either of the two materials, raising the specter of greater instability in the region.
North Korea tested its first nuclear device in 2006 and a second one on May 25 in defiance of a U.N. ban, attracting the latest sanctions that aim to stop the reclusive communist nation's weapons exports and financial dealings. They also allow inspections of suspect cargo in ports and on the high seas.
"The cargo inspection provisions of the U.N. Resolution (1874) passed Friday, are seen by Kim Jung Il's government as a threat to its nuclear program," Falk reports, "and, if enforced, increase the possibility of a confrontation and raise the stakes."
Despite the U.N. sanctions, North Korea said it was "an absolutely impossible option" for it to abandon its nuclear programs, which it called a "self defensive measure" against a hostile U.S. policy and its nuclear threat against the North.
"An attempted blockade of any kind by the U.S. and its followers will be regarded as an act of war and met with a decisive military response," it said without elaborating.
North Korea describes its nuclear program as a deterrent against possible U.S. attacks. Washington says it has no intention of attacking and has expressed fear that North Korea is trying to sell its nuclear technology to other nations.
The statement also said that "the whole amount of the newly extracted plutonium (in the country) will be weaponized," and that "more than one third of the spent fuel rods has been reprocessed to date."
North Korea is believed to have enough plutonium for at least half a dozen atomic bombs. The North also has about 8,000 spent fuel rods which, if reprocessed, could allow the country to harvest 13-18 pounds of plutonium - enough to make at least one nuclear bomb, experts say.
Under a 2007 six-nation deal, North Korea agreed to disable its main nuclear complex in Yongbyon north of Pyongyang in return for 1 million tons of fuel oil and other concessions. In June 2008, North Korea blew up the cooling tower there in a dramatic show of its commitment to denuclearization.
But disablement came to halt a month later as Pyongyang wrangled with Washington over how to verify its past atomic activities. The latest round of talks, in December, failed to push the process forward.