[1] Active in local Irish-American organizations as a young man, O'Dwyer had a law practice in downtown Brooklyn while his brother William served as the borough's magistrate.

As chairman of the American Friends of Irish Neutrality, he traveled the United States to speak with and rally pro-neutrality (particularly Irish-American) groups.

[10] O'Dwyer publicly opposed library censorship of books,[11] defended labor union leaders and alleged anarchists,[12][13] supported the left-wing American Labor Party,[14] challenged racial segregation in New York housing and on Wall Street,[15][16][17] fought for the creation of Israel,[18][19] organized Black voters in the South,[20] represented striking Kentucky coal miners, argued for the rights of mainland Puerto Rican voters before the U.S. Supreme Court,[21] sued New York City to keep transit fares low,[22] and led an April 1969 antiwar march of tens of thousands of protesters from Times Square to Central Park.

[23] O'Dwyer's downtown Manhattan law office famously served as the resting place of the acerbic writer Dorothy Parker, whose ashes were kept in a filing cabinet there for decades.

In 1948, he narrowly lost an election for the U.S. House of Representatives seat on Manhattan's Upper West Side to the Republican incumbent Jacob K.

In 1968, in opposition to U.S. involvement in the Vietnam War and with the support of presidential candidate Eugene McCarthy, O'Dwyer ran in the Democratic Party primary for U.S.

[29] Again he found his candidacy opposing popular Republican Party incumbent Jacob Javits and again O'Dwyer lost in the general election.