[1] Niles was born in Chester County, Pennsylvania, to a Quaker family, although his father quit the church to fight in the American Revolutionary War.

Niles edited and published the Weekly Register until 1836, making it into one of the most widely circulated magazines in the United States and himself into one of the most influential journalists of his day.

The Niles' Weekly Register covered not only politics, but economics, science, technology, art, and literature.

In the Register's discourse of politics, Niles used what he called "magnanimous disputation", trying to present the arguments of both sides fairly and objectively, a policy which has made the paper an important source for the history of the period.

Niles foresaw the possibility of the American Civil War as early as 1820, and published articles in the Register which suggested efforts the South could make in modernizing their economy to a form which was not fully dependent on slavery, publishing efforts which he hoped would help avoid conflict between the North and South.