[5] O'Neill's record as the longest-serving female legislator in Illinois history for her service during 19 General Assemblies was surpassed when Barbara Flynn Currie was reelected to a twentieth term.

[7][8] O'Neill was inspired by the political success of Jeannette Rankin of Montana, who in 1916 was the first woman elected to the United States House of Representatives.

During her early career, she focused on equal rights for women, introducing the eight-hour work day[9] and improving state assistance for disabled children.

[11] She lost the Republican primary, but entered that year's United States Senate election as an independent candidate with the backing of the Illinois chapter of the Anti-Saloon League.

McCormick, who defeated Charles S. Deneen in the Republican primary, lost the election to Democrat J. Hamilton Lewis with O'Neill finishing a distant third.

In 1935, a Democratic lawmaker called for O'Neill to be expelled from the House after she and a colleague introduced a resolution critical of President Franklin D. Roosevelt and Governor Henry Horner.

In the general election, she easily defeated Democratic candidate and former state legislator Joseph Sam Perry of Glen Ellyn.

[19] O'Neill defeated the party's preferred slate of delegates to the 1956 Republican National Convention, which re-nominated Dwight Eisenhower.

[7] In 1958, 29 year old DuPage County Assistant State's Attorney, Harris Fawell challenged O'Neill in the 41st district Republican primary for the Illinois Senate.

[7] In 1960, she founded the Northern Illinois Conservatives with the hopes of creating a voting bloc that would move the Republican Party further right.