The publishers and staff of the journal were, for the most part, Protestant or secular Liberals (in a 19th-century understanding of the word). The Harpers, for example, were Methodists, and long-time editor George William Curtis was a Unitarian. They believed that the Roman Catholic Church was an antiquated, authoritarian institution ("Medieval" would be a common term of derision) that stood against the "Modernism" of a free, progressive society and democratic political institutions. Irish-Catholics were often suspected of being loyal primarily to the Vatican, rather than to the United States, and of being unassimilable by nature or stubborn will. Protestant Irish, on the other hand, were praised, on the few occasions when they were considered by the paper.

Furthermore, Irish-Catholics were overwhelmingly aligned with the Democratic party. They were more actively involved in politics than many other ethnic groups at the time, and constituted a key voting bloc for the Democratic party at all levels: urban, state, and national. Beginning with the 1864 presidential election and ending with the 1884 presidential election, Harper's Weekly was a staunchly pro-Republican newspaper. Granted, it was more independent than a mere party-organ would be, thanks in large part to Curtis's editorials, but it still could be counted on to promote Republican positions and candidates and to attack Democratic policies and candidates. To the Harper's Weekly publishers and staff, the Democratic party was the party of slavery, secession, civil war, vote fraud, political corruption, and violence. The Irish were often considered to be pugnacious by nature or nurture, and were believed to play a major role in the violence and corruption of the Democratic party, especially through urban political machines, such as New York City's Tammany Hall.