James Sykes (March 27, 1761 – October 18, 1822) was a Delaware physician and politician.

James Sykes, Jr. was born near Dover, Delaware on March 27, 1761, the son of Delaware lawyer James Sykes, Sr. After studying medicine at Williams College and under Dr. Joshua Clayton , he set up practice in Cambridge, Maryland. During his time in Cambridge, Sykes met and married Elizabeth Goldsborough. Sykes returned to Dover after four years, going on to become one of the state's most renowned surgeons.

In 1791 the Delaware General Assembly appointed Sykes to help manage a lottery to raise one thousand pounds to defray expenses incurred in constructing a new state house. He was chosen as a Presidential Elector in 1792 and cast his vote for George Washington. Sykes served as clerk of the Delaware State House of Representatives in 1796. He served in the Delaware State Senate from 1793 – 1795 and from 1797 – 1801, serving as Speaker from 1800 – 1801.

In 1801, Governor Richard Bassett resigned following his appointment as United States Circuit Judge by President John Adams. As the Speaker of the Senate, Sykes was next in line of succession to the Governorship. He took office as acting governor on March 4, 1801. Sykes chose not to run for election, and returned to the Senate on January 19, 1802. Sykes remained in the Senate until 1812.

Sykes moved to New York in 1814, but returned to Dover in 1820. He died in Dover on October 18, 1822 at the age of 61. Sykes is buried at Christ Episcopal Church in Dover. Sykes's home is currently an office building on The Green in Dover.

Sykes had three children; James, Anna Matilda, and William. His son James became a physician in Dover and his son William was the father of American Civil War Major General George Sykes.