He was acting governor of New York from who resided inside Fort Amsterdam in1760 to 1762 (replaced by Robert Monckton in 1762) and again from 1763 to 1765, and from 1769 to 1770 after Henry Moore's death, by which time he was eighty years old.

He served as the first colonial representative to the Iroquois Confederacy, an experience that resulted in his writing The History of the Five Indian Nations (1727), the first book on the subject.

In summer 1775, the British authority in New York came to its end as America entered into Revolutionary era, and Colden retired from public life.

In 1743, he published a series of essays noting the correlation between filthy living conditions and high rates of disease in New York City.

Colden's essays were critical for establishing the sanitation efforts of New York City, and a milestone in the development of the field of public health.

He devoted much of his adult life to correcting the alleged mistakes and in 1751 published in London his views on the subject, Principles of Action in Matter.

[11] In his 1727 book, The History of the Five Indian Nations, about the Iroquois, Colden suggested that a canal be built to connect the Hudson River with the Great Lakes to enable increased trade with Native Americans, for fur, and western settlers for agricultural products.

Because this women was often unruly with an "alusive tongue", Colden separated her from her children out of concern that she might be a bad influence on them, and proposed to exchange her for a cargo of 'white muscovado' sugar.

Please likewise to buy mee a negro Girl of about thirteen years old[...] my wife has told you that she designes her Chiefly to keep the children & to sow & theirfore would have her Likely & one that appears to be good natured.'

[14][15] In November 1715, while visiting Scotland, Colden married Alice Chrystie of Kelso; together they had ten children, including:[16] He died in Spring Hill near Flushing in Queens County on Long Island in New York.