Blackmer was born and raised in Salisbury, North Carolina, As a young man in his late teens, he went to New York City looking for acting work in the theater. While there, he took jobs at various film studios at the then motion picture capital, Fort Lee, New Jersey, including a bit part in the highly popular 1914 serial, The Perils of Pauline.

He made his Broadway debut in 1917, but his career was interrupted by service in the U.S. military in World war I. After the war, he returned to the theatre and in 1929 returned to motion pictures and went on to be a major character actor in more than 120 films.

He won the 1950 Tony Award for Best Actor (Drama) for his role in the Broadway play, Come Back, Little Sheba.

In film, Blackmer is remembered for his more than a dozen portrayals of U.S. President Theodore Roosevelt and for his role in the Academy award-winning 1968 Roman Polanski film about urban New York witches Rosemary's Baby, in which he played an over-solicitous neighbour, married to an even more over-solicitous neighbor, played by Ruth Gordon (who won an Oscar for her performance).

A humanitarian, Sidney Blackmer served as the national vice president of the United States Muscular Dystrophy Association.

On his passing in 1973, Sidney Blackmer was interred in the Chestnut Hill Cemetery in his hometown of Salisbury, North Carolina.

For his contribution to the motion picture industry, Sidney Blackmer has a star on the Hollywood Walk of Fame at 1625 Vine Street.

In 1972, he was honored with the North Carolina Award in the Fine Arts category. It is the state of North Carolina's highest civilian award.