At age 15 Rice entered the University of Denver. Although she had earlier considered a career as a concert pianist, she turned to the study of international relations, earning a bachelor's degree in the field in 1974. She later obtained a master's degree (1975) in economics from the University of Notre Dame and a doctorate (1981) in international studies from the University of Denver, where her specialty was eastern and central Europe and the Soviet Union, including military and security affairs. Rice joined the faculty of Stanford University in 1981. In 1986 she served as an assistant to the Joint Chiefs of Staff on nuclear strategy, and during the administration of Pres. George Bush (Bush, George) she was director for Soviet and eastern European affairs for the National Security Council (NSC) and a special assistant to the president. In 1991 Rice returned to Stanford and in 1993 began a six-year tenure as provost, during which time she balanced the university's budget and revamped the curriculum for undergraduates.

In 1999 Rice left Stanford to become foreign policy adviser to the presidential campaign of George W. Bush, and upon his election she was named head of the NSC, the first woman to hold this position. Following the September 11 attacks in 2001, she proved to be an important and influential adviser to Bush. She supported the U.S.-led attacks on terrorist and Taliban targets in Afghanistan (2001) and aligned herself with hard-liners who advocated the overthrow of Iraqi President Ṣaddām Ḥussein. When the administration drew criticism for the Iraq War (2003) and the handling of terrorist threats prior to September 11, 2001, Rice vigorously defended the president's policy.

Rice's writings include The Soviet Union and the Czechoslovak Army, 1948–1983: Uncertain Allegiance (1984) and Germany Unified and Europe Transformed: A Study in Statecraft (1995, with Philip Zeliko).