Rice called on the West to stand up to Russian aggression after its invasion of Georgia last month.
"The attack on Georgia has crystallized the course that Russia's leaders are taking and brought us to a critical moment for Russia and the world," she said in a speech at a German Marshall Fund event. "Our strategic goal now is to make it clear to Russia's leaders that their choices could put Russia on a one-way path to self-imposed isolation and international irrelevance."
The remarks reflected an escalation of rhetoric in a relationship that has deteriorated markedly since last month's war and Moscow's recognition of two breakaway regions of Georgia.
Rice, who called Russian Foreign Minister Sergey Lavrov ahead of the speech Thursday, mocked Russia for its international isolation and attempt to project its influence into America's backyard by cultivating U.S. foes like Cuba and Venezuela.
Rice noted sarcastically that Nicaragua and the Palestinian terror group Hamas are the only other entities that have so far recognized the independence of Abkhazia and South Ossetia.
"A pat on the back from Daniel Ortega and Hamas is not a diplomatic triumph," Rice said, referring to the president of Nicaragua, a longtime foe of the United States.
The Russian Foreign Ministry had no immediate comment about the speech. However, speaking at diplomatic event Thursday, Russian President Dmitry Medvedev said that relations with the U.S. remains a priority for Russia, adding that "we have every opportunity to develop a constructive long-term dialogue."
"The history of U.S.-Russian relations has seen quite a few acute situations. But common sense, pragmatism and respect for each other's interests always prevailed in the end," he said.
She also mocked Russia's recent military exercises with another U.S. foe, Venezuela, suggesting that despite its crushing victory over Georgia, Russia's armed forces have still not recovered from their decline as the Soviet Union collapsed.
"We are confident that our ties with our neighbors, who long for better education, better health care, better jobs, and better housing, will in no way be diminished by a few, aging Blackjack bombers, visiting one of Latin America's few autocracies" she said.
The speech promised support for Georgia, highlighting promises of economic aid by the United States and European countries.
"In contrast to Georgia's position, Russia's international standing is worse than at any time since 1991," she said. "And the cost of this self-inflicted isolation has been steep."
U.S. officials have pointed to Russian economic problems since the invasion as a sign of the country's isolation. Russia is struggling to stem a dizzying plummet in share prices and restore confidence in the economy, as investors have sharply pulled capital out of the country in recent weeks amid a broader international credit crisis.
Rice, an academic specialist on the Soviet Union, said that as in the Cold War, the United States would seek to maintain cultural ties with Russia regardless of tensions.
"We will continue to sponsor Russian students and teachers, judges and journalists, labor leaders and democratic reformers who want to visit America," she said. "We will continue to support all Russians who want a future of liberty for their great nation."
The speech held out hope that Russia would change its course.
"Whether Russia's leaders overcome their nostalgia for another time and reconcile themselves to the sources of power and the exercises of power in the 21st century; this remains to be seen," she said. "The decision is clearly Russia's, and Russia's alone."