Al-Wazir became a refugee when his family was expelled from Ramla during the 1948 Arab–Israeli War, and began leading a minor fedayeen force in the Gaza Strip. In the early 1960s he established connections for Fatah with Communist regimes and prominent third-world leaders. He opened Fatah's first bureau in Algeria. He played an important role in the 1970–71 Black September clashes in Jordan, by supplying besieged Palestinian fighters with weapons and aid. Following the PLO's defeat by the Jordanian Army, al-Wazir joined the PLO in Lebanon.
Prior to and during Israel's 1982 invasion of Lebanon, al-Wazir planned numerous attacks inside Israel against both civilian and military targets. He prepared Beirut's defense against incoming Israeli forces. Nonetheless, the Israeli military prevailed and al-Wazir was exiled from Lebanon with the rest of the Fatah leadership. He settled in Amman for a two-year period and was then exiled to Tunis in 1986. From his base there, he started to organize youth committees in the Palestinian territories; these eventually became the backbone of the Palestinian forces in the First Intifada. However, he did not live to command the uprising. On 16 April 1988, he was assassinated at his home in Tunis, by Israeli commandos.
Khalil al-Wazir was born in 1935 to Muslim parents in the city of Ramla, Palestine, then under British Mandatory rule. His father, Ibrahim al-Wazir, worked as a grocer in the city. Al-Wazir and his family were expelled in July 1948, along with another 50,000–70,000 Palestinians from Lydda and Ramla, following Israel's capture of the area during the 1948 Arab-Israeli War. They settled in the Bureij refugee camp in the Gaza Strip, where al-Wazir attended a secondary school run by UNRWA. While in high school, he began organizing a small group of fedayeen to harass Israelis at military posts near the Gaza Strip and the Sinai Peninsula.
In 1954 he came into contact with Yasser Arafat in Gaza; al-Wazir would become Arafat's right-hand man later in his life. During his time in Gaza, al-Wazir became a member of the Egyptian Muslim Brotherhood, and was briefly imprisoned for his membership with the organization, as it was prohibited in Egypt. In 1956, a few months after his release from prison, he received military training in Cairo. He also studied architectural engineering at the University of Alexandria, but he did not graduate. Al-Wazir was detained once again in 1957 for leading raids against Israel and was exiled to Saudi Arabia, finding work as a schoolteacher. He continued to teach after moving to Kuwait in 1959.
Al-Wazir used his time in Kuwait to further his ties with Arafat and other fellow Palestinian exiles he had met in Egypt. He and his comrades founded Fatah, a Palestinian nationalist guerrilla and political organization, sometime between 1959–60. He moved to Beirut after being put in charge of editing the newly formed organization's monthly magazine Filastinuna, Nida' al-Hayat ("Our Palestine, the Call to Life"), as he was "the only one with a flair for writing."