Perino was born in Evanston, Wyoming, and grew up in Denver, Colorado. She attended Ponderosa High School in Parker, Colorado, a suburb of Denver. Perino graduated from the University of Southern Colorado (now known as Colorado State University-Pueblo) in 1994 with a bachelor's degree in mass communications and minors in both political science and Spanish. While attending the university, Perino was active on the debate team and with KTSC-TV, the campus-based PBS affiliate where she served as host of Capitol Journal, a weekly summary of Colorado politics, and producer of Standoff, a weekly public affairs program. From there, Perino attended graduate school at the University of Illinois at Springfield (UIS). Perino obtained her masters at UIS in Public Affairs Reporting while also working as a daily reporter covering the Illinois Capitol for WCIA-TV, a CBS affiliate.
Perino then went on to work in Washington, D.C., for Representative Scott McInnis (R, retired) of Colorado as a staff assistant before serving nearly four years as the press secretary for Rep. Dan Schaefer (R-CO-Retired), who then chaired a House Commerce subcommittee on Energy and Power.
After Representative Schaefer announced his retirement, Perino moved to England to marry businessman Peter McMahon. After a year in England, Perino and McMahon moved back to the United States and resided in San Diego, California, for three years. During that time, Perino worked in the field of high-tech public affairs.
In November 2001, Perino returned to Washington, D.C. to serve as a spokesperson for the Department of Justice. Several months later, she was asked to join the White House where she served as the Director of Communications for the White House Council on Environmental Quality (CEQ). By statute, the CEQ oversees the implementation of the National Environmental Policy Act, where all federal agencies must complete environmental assessments on their activities before they take action.
On March 31, 2006, President George W. Bush named Perino as Deputy Assistant to the President and Deputy Press Secretary. In the role, Perino communicated many times a day with the President's director of communications, his press secretary and his director of media affairs, handling all environment-related media calls for the White House, as well as serving as the spokesperson for the White House on environmental issues. In addition, she served as the coordinator for all agencies on environment, energy and natural resource issues, as well as reviewing and approving the agencies' major announcements, while keeping the other White House offices apprised of CEQ actions.