Manatos served as a U.S. Senate committee staff director and an assistant secretary in the President Jimmy Carter Administration. He founded the Washington, D.C., public affairs company of Manatos & Manatos in 1983, of which he continues to be president. The Washington Post described the firm as “one of Washington’s most powerful lobbying firms.”

Working closely with the Greek Orthodox Archdiocese of America, on whose national council he serves and as a regional commander of the Order of St. Andrew, his firm created and maintains an annual meeting with each president of the United States for 27 years with the Greek-American community. Manatos managed the legislation that secured the Congressional Gold Medal for Ecumenical Patriarch Bartholomew, secured use of the U.S. Capitol Rotunda for honoring Ecumenical Patriarch Dimitrios, the second time in history the Rotunda was used to honor a living person. He also orchestrated efforts producing letters to the president advocating religious freedom for the Ecumenical Patriarchate, signed by 90 of the 100 senators and more than 291 members of Congress.

Manatos has testified before the U.S. Congress and has been a guest columnist for The Washington Post, The New York Times, and other national publications. Manatos co-hosts an annual Washington dinner for the THEA Foundation with former President Bill Clinton.