Emma became engaged to the king of Hawaii, Alexander Liholiho. At the engagement party, a Hawaiian charged that Emma's Caucasian blood made her unfit to be the Hawaiian queen and her lineage was not suitable enough to be Alexander Liholiho's bride; she broke into tears and the king was infuriated. On June 19, 1856, she married Alexander Liholiho, who a year earlier had assumed the throne as Kamehameha IV. He was also fluent in both Hawaiian and English. Each nation and even the Chinese hosted balls and celebrations in honor of the newlyweds. Two years later on May 20, 1858 Emma gave birth to a son, Prince Albert Edward Kamehameha.

During her reign, the queen tended palace affairs, including the expansion of the palace library. During her reign and after, she was known for her humanitarian efforts. Inspired by her adoptive father's work, she encouraged her husband to establish a public hospital to help the Native Hawaiians who were in decline due to foreign-borne diseases like smallpox. In 1859, Emma established Queen's Hospital and visited patients there almost daily whenever she was in residence in Honolulu. It is now called the Queen's Medical Center.