The son of William Van Wyck and brother of Augustus Van Wyck, he was prepared for college at the Wilson Academy in North Carolina, and later graduated from Columbia, where he was valedictorian of his class. He then passed a number of years in mercantile life, after which he became an able lawyer and enjoyed a large practice for many years. Later, he was elected Judge of the City Court of New York, becoming thereafter Chief Justice. He resigned to accept the Democratic Party nomination for Mayor of Greater New York, and was elected by a very large majority. He served as mayor of New York City between 1898 and 1901 and was the first mayor to govern New York City after its five boroughs had been consolidated into a single city.

He was a member of the Holland Society, of which he became President. He belonged to many of the social clubs of the city, and was prominent in Masonic circles, being a member of The Ancient Lodge, New York City. For many years he took a most active interest in party matters, attending many conventions, State and national. He subsequently became intensely fond of traveling, and indulged in that pleasure to a very large extent.

As Mayor, he brought together the innumerable municipal corporations comprising the greater city, adjusting their finances and bringing order out of almost total chaos. He also initiated the construction of the first subway railroad in Manhattan, and provided for the construction of the proposed Brooklyn Tunnel.

Van Wyck is generally regarded as a colorless mayor, selected by the sachems (leaders) of Tammany Hall as a man who would do little to interfere with their running of the city. He was, however, no more averse than many of his colleagues to enriching himself once actually in office. Initially highly popular as a result of his reversal of the various reforms introduced by the preceding Fusion administration, Van Wyck's mayoralty foundered on the issue of the so-called 'Ice Trust' scandal on 1900. One of the most serious reverses ever suffered by a Tammany mayor, the scandal followed on the revelation, made by the New York World, that the American Ice Company of Charles W. Morse planned to double the price of ice from 30 to 60 cents per hundred pounds. In the era before refrigeration, this was a potentially deadly decision, since ice was the only preservative available to keep food, milk and medicines fresh, and the new price would have put the product out of the reach of many of the city's poor – Tammany's main power base.

Public outcry was such that American Ice was forced to reverse its decision, but not before Van Wyck's political rivals had forced an investigation that eventually revealed not only that American Ice had secured an effective monopoly over the supply of its product to the city – it was the only company with rights to land ice at New York piers – but also that Van Wyck, whose salary as mayor was only $15,000, owned, and had apparently not paid for, $680,000 worth of American Ice stock.

The ice trust scandal destroyed Van Wyck's political career and was generally reckoned to have cost Tammany the elections of 1901, which went to the Fusion reformist slate led by Seth Low. The New York Times, looking back two years later, characterized the Van Wyck administration as one mired in "black ooze and slime". However, in an investigation conducted by Governor Theodore Roosevelt, it was determined that Van Wyck had not been personally implicated in the Ice Trust Scandal.

In 1906, Van Wyck moved to Paris, France, where he died at the age of 69 on November 14, 1918. The funeral was held at American Holy Trinity Church; he is buried at Woodlawn Cemetery in the Bronx.

His name lives on in New York City:

• Middle School 217 Q. at 85-05 144 Street in Jamaica, Queens is the Robert A. Van Wyck Middle School.
• Van Wyck Blvd. (also called Briarwood - Van Wyck) is a stop on the F-train and sometimes the E-train.
• Jamaica - Van Wyck is a stop on the E-train.
• The Van Wyck Expressway runs in a north - south direction through Queens County from Kennedy Airport in the south to the Whitestone Expressway in the north.