Khalil Sakakini was born in Jerusalem on January 23, 1878. He received his schooling there, at the Greek Orthodox school, at the CMS College, and at the Zion English College where he read Literature.

Following the death of his father, Sakakini traveled to the United Kingdom and from there to the United States to study education. However, he was unable to pursue his studies due to financial constraints and returned to Palestine in 1908. During his American stay, he was active teaching Arabic, translating, and contributing to the Arabic literary magazines of the East Coast. Upon his return, he worked as a journalist for the Jerusalem newspaper Al Asmai' and taught Arabic at the renowned Jerusalem Salahiyya school, and to expatriates at the American Colony

In 1909, he founded the Dusturiyyah school, which became known for its Arab nationalism. He pioneered a system he was to use later: there were no grades, prizes or punishments for students; and there was an emphasis on music education and athletics.

Sakakini led a movement to reform and Arabize the Greek Orthodox Church in Palestine, and wrote a pamphlet in 1913 titled "The Orthodox Renaissance in Palestine", which led to his excommunication. Ottoman authorities arrested him in 1917 and jailed him in Damascus for sheltering a Jewish-Polish immigrant who was -unbeknownst to him- an American spy. After his release, he joined the ranks of the Arab Revolt, which anthem he wrote.

In 1919 Khalil Sakakini went to work for the Educational Authority of Palestine in Jerusalem, and was appointed head of the Jerusalem Teachers’ College. He went on to be appointed Inspector for Education for Palestine, a post he held for twelve years, until his resignation in protest at the appointment of Herbert Samuel as High Commissioner in Palestine. At the same time, he wrote political commentaries for the newspapers Al Muqtataf, Al Hilal and Al Siyassa al Usbu`iyya, composed a number of patriotic poems, and spoke at political rallies. In 1925, Khalil Sakakini founded the Wataniyya school, and in 1938 the Nahda College in Jerusalem.

Khalil Sakakini's wife, Sultana, died in October 1939. He lived in consummate grief since, and wrote a number of poems eulogizing her. He also wrote his will and obituary. In 1948, a few days before the city was divided and its western part seized by the Israelis, the Sakakinis fled Jerusalem, the last Palestinian family remaining in the Qatamon quarter ravaged by Israeli mortar attacks. They left with only their personal effects, and sought refuge in Cairo where Sakakini was nominated by the Egyptian writer Taha Hussein to join the Arabic Language Academy. The sudden death of his son Sari in 1953 left him in poor health, and he died three months later on August 13, 1953.