Born in Thrace, as a young man Noli wandered throughout the Mediterranean Basin, living in Athens, Greece, and Alexandria, Egypt and supporting himself as an actor and translator. Through his contacts with the Albanian expatriate movement, he became an ardent supporter of the country's nationalist movement, and moved to Boston in 1906 in order to mobilize the Albanian emigrant community. At that time, Albanian Christians were part of the Greek Orthodox Church, which was vehemently opposed to the nationalist cause. When a Greek Orthodox priest refused to perform the burial rites for a member of the Albanian community because of his nationalist activity, Noli and a group of nationalists in New England created the independent Albanian Orthodox Church. Noli, the new church's first clergyman, was consecrated as a priest in 1908.
That same year, Noli began studying at Harvard, completing his degree in 1912. He returned to Europe to promote Albanian independence, setting foot in Albania for the first time in 1913. He returned to the United States during World War I, serving as head of the Vatra organization, which effectively made him leader of the Albanian diaspora. His diplomatic efforts in the United States and Geneva won the support of President Woodrow Wilson for an independent Albania, and in 1920 earned the new nation membership in the fledgling League of Nations. Though Albania had already declared its independence in 1912, membership in the League of Nations provided the country with the international recognition it had failed to obtain until then.
In 1921 Noli entered the Albanian parliament as a representative of the liberal Vatra party, the chief liberal movement in the country. He served briefly as foreign minister in the government of Xhafer Ypi. This was a period of intense turmoil in the country between the liberals, represented by Vatra, and the conservatives, led by prime minister Ahmet Zogu. After a botched assassination attempt against Zogu, the conservatives revenged themselves by assassinating another popular liberal politician, Avni Rustemi. Noli's speech at Rustemi's funeral was so powerful that liberal supporters rose up against Zogu and forced him to flee to Yugoslavia (March 1924). Zogu was succeeded briefly by his father-in-law, Shefqet Verlaci, and by the liberal politician Ilias Vrioni; Noli was named prime minister and regent on July 17, 1924.
Despite his efforts to reform the country, Noli's "Twenty Point Program" was unpopular, and his government was overthrown by groups loyal to Zogu on Christmas eve of that year. Two weeks later, Zogu returned to Albania, and Noli fled to Italy under sentence of death. He moved back to the United States in 1932 and formed a republican opposition to Zogu, who had since proclaimed himself King Zog I. Over the next years, he continued his education, studying and later teaching Byzantine music, and continued developing and promoting the autocephalic Albanian Orthodox Church he had helped to found. While in exile, he also managed to maintain ties with the communist government of Enver Hoxha that emerged after World War II and urged the American government to recognize the new regime in Albania. Toward the end of his life he retired to Fort Lauderdale, Florida, where he died in 1965.