Charles was commissioned governor of Maryland on September 14, 1661, and served as such until the death of his father, November 30, 1675. Upon his father's death he succeeded to the proprietorship of the province, and the third Lord Baltimore.

Being a Catholic, his position as governor and as proprietor came with many problems, as Protestants in the colony outnumbered the Catholics ten to one. Additionally, the ranks of the dissatisfied were increased with recruits from those who had come to the colony as convicts or as indentured servants. His problems continued with the Susquehanna Indians, who were hostile.

Because of a boundary dispute with William Penn, Calvert was required to travel to England where his troubles continued in the Protestant Revolution of 1688, as well as the antagonistic attitude of King William III toward proprietary charters. King William III ascended to the throne jointly with his wife, Queen Mary II in 1688, upon the death of King James II. Although executive power was given to William, they served together from 1689 to 1694. Upon Mary's death in 1694, William III ruled alone until his death in 1702. William III was succeeded by Queen Anne, who ruled from 1702 to 1714. Although Charles was industrious in coping with these many difficulties, he did so with a bad temper, especially toward any opposition. In 1670, following a heated experience with the Assembly in 1669, votes in the Assembly were restricted to those freemen who had at least fifty acres of land, or who had an estate worth at least forty pounds sterling. Meanwhile, the practice began of summoning to the Assembly only one-half of the delegates who had been elected. Calvert was accused of abusing his privilege of appointing sheriffs to control elections. In 1672, Charles caused the election of Thomas Notley, a strong supporter of Calvert, as speaker. When delegates to the Assembly did not see issues Calvert's way, he would summon them to his chamber, where he prevailed upon them to yield. Calvert had a habit of vetoing acts in the Assembly years after they had been passed.

Charles Calvert was married four times. His second wife, Jane, was the daughter of Vincent Lowe and the widow of Henry Sewall. Charles and Jane had several children, one of which was Benedict Leonard Calvert, the fourth Lord Baltimore. Charles' children were intent on making government a family affair. This attitude was successful for a short time, but passed to incompetent guardians soon after Charles's departure from England in 1684, when Charles went to defend his charter and territory from attacks by William Penn. Calvert's charter and territory were overthrown in 1689 by a Protestant association led by the irreverent John Coode. In 1692 a royal government was established.