Isenhour also previously worked as executive director of the Pennsylvania House Democratic Campaign Committee, and started a political consulting firm with former state party chairman T.J. Rooney.

[8] From 1991 to 1995, Isenhour served as Chief of Staff to House Minority Leader Tom Sawyer,[5][9][10] where she worked with Democratic and Republican lawmakers alike to advance legislation, served as a liaison between Sawyer and other officials, and worked with members of leadership and committees to develop legislative strategies and build coalitions.

She described it as an attempt to avoid a repeat of 1994 elections, in which Democrats suffered major losses in both federal and state offices during the Republican Revolution.

[5][14] Isenhour assisted with Bob Casey, Jr.'s successful 2006 campaign against Republican incumbent Rick Santorum,[23] served as political adviser to state House Democratic Leader Frank Dermody,[1] and ran Governor Ed Rendell's successful 2006 re-election campaign against challenger Lynn Swann,[15][24] after which she helped plan Rendell's 2007 inauguration.

[1] Isenhour was also chosen as the Pennsylvania state director for Hillary Clinton's 2008 presidential campaign,[3][6][14] after Rendell recommended her for the position.

[27] There was talk of Isenhour continuing to work with the Clinton administration after the primary, but she instead returned to her position with the Pennsylvania Democratic Party.

[23] Isenhour also taught about electoral politics at other educational institutions, including the University of Pennsylvania, Central Penn College and The Washington Center.

[32] After Wolf's successful election, Isenhour co-chaired his inaugural committee,[34][35] then worked as his Secretary of Legislative Affairs,[25][31] serving as a liaison during negotiating sessions at the Pennsylvania General Assembly, and providing key planning during the governor's budget strategy.

[24] Political reporter John L. Micek wrote of Isenhour: "She is in the unique position of having to work with Republicans she once ran campaigns against.

[3][24][31] Wolf called Isenhour "one of my closest advisors" and "a valuable part of my administration",[14] and said she "really understands how the politics of this place actually works.

[6] The Butler Eagle wrote an editorial criticizing the appointment due to her position on the Planned Parenthood of Pennsylvania board, in light of a national controversy over undercover videos about the group's alleged sale of aborted fetal body parts.

[6][24] In October 2015, four months into the state budget impasse, Isenhour issued a memo notifying Wolf's administration of a hiring freeze and travel ban.

[37] On February 3, 2016, Isenhour notified the state Public Employee Retirement Commission that, under Wolf's orders, all employment of its staff would be discontinued.