The Gibrans settled in Boston's South End, at the time the second-largest Syrian-Lebanese-American community in the United States. Due to a mistake at school, he was registered as "Kahlil Gibran". His mother began working as a seamstress peddler, selling lace and linens that she carried from door to door. Gibran started school on September 30, 1895. School officials placed him in a special class for immigrants to learn English. Gibran also enrolled in an art school at Denison House, a nearby settlement house. Through his teachers there, he was introduced to the avant-garde Boston Artist, Photographer, and publisher Fred Holland Day, who encouraged and supported Gibran in his creative endeavors. A publisher used some of Gibran's drawings for book covers in 1898.

Gibran's mother, along with his elder brother Peter, wanted him to absorb more of his own heritage rather than just the Western aesthetic culture he was attracted to. Thus, at the age of fifteen, Gibran returned to his homeland to study at a Maronite-run preparatory school and higher-education institute in Beirut, called "al-Hikma" (The Wisdom). He started a student literary magazine with a classmate and was elected "college poet". He stayed there for several years before returning to Boston in 1902, coming through Ellis Island (a second time) on May 10. Two weeks before he returned to Boston, his sister Sultana died of tuberculosis at the age of 14. The year after, Peter died of the same disease and his mother died of cancer. His sister Mariana supported Gibran and herself by working at a dressmaker's shop.

The nature of their romantic relationship remains obscure; while some biographers assert the two were lovers but never married because Haskell's family objected, other evidence suggests that their relationship never was physically consummated. Gibran and Haskell were engaged briefly but Gibran called it off. Gibran didn't intend to marry her while he had affairs with other women. Haskell later married another man, but then she continued to support Gibran financially and to use her influence to advance his career. She became his Editor, and introduced him to Charlotte Teller, a Journalist, and Emilie Michel (Micheline), a French Teacher, who accepted to pose for him as a model and became close friends. In 1908, Gibran went to study art in Paris for two years. While there he met his art study partner and lifelong friend Youssef Howayek. While most of Gibran's early writings were in Arabic, most of his work published after 1918 was in English. His first book for the publishing company Alfred A. Knopf, in 1918, was The MadMan, a slim volume of aphorisms and parables written in biblical cadence somewhere between poetry and prose. Gibran also took part in the New York Pen League, also known as the "immigrant poets" (al-mahjar), alongside important Lebanese-American authors such as Ameen Rihani, Elia Abu Madi, and Mikhail Naimy, a close friend and distinguished master of Arabic literature, whose descendants Gibran declared to be his own children, and whose nephew, Samir, is a Godson of Gibran's.

Nevertheless, Gibran called for the adoption of Arabic as a national language of Syria, considered from a geographic point of view, not as a political entity. When Gibran met 'Abdu'l-Bahá in 1911–12, who traveled to the United States partly to promote peace, Gibran admired the teachings on peace but argued that "young nations like his own" be freed from Ottoman control. Gibran also wrote the famous "Pity The Nation" poem during these years, posthumously published in The Garden of The Prophet.

Mary Haskell Minis (she wed Jacob Florance Minis in 1923) donated her personal collection of nearly one hundred original works of art by Gibran to the Telfair Museum of Art in Savannah, Georgia in 1950. Haskell had been thinking of placing her collection at the Telfair as early as 1914. In a letter to Gibran, she wrote "I am thinking of other museums ... the unique little Telfair Gallery in Savannah, Ga., that Gari Melchers chooses pictures for. There when I was a visiting child, form burst upon my astonished little soul." Haskell's gift to the Telfair is the largest public collection of Gibran's visual art in the country, consisting of five oils and numerous works on paper rendered in the artist's lyrical style, which reflects the influence of symbolism. The Future American royalties to his books were willed to his hometown of Bsharri, to be "used for good causes".

Gibran died in New York City on April 10, 1931, at the age of 48. The causes were cirrhosis of the liver and tuberculosis due to prolonged serious alcoholism. Gibran started drinking seriously during or after publication of The Prophet. Several years before his death, he locked himself in his apartment, away from visitors, drinking all day. Gibran expressed the wish that he be buried in Lebanon. This wish was fulfilled in 1932, when Mary Haskell and his sister Mariana purchased the Mar Sarkis Monastery in Lebanon, which has since become the Gibran Museum. Written next to Gibran's grave are the words "a word I want to see written on my grave: I am alive like you, and I am standing beside you. Close your eyes and look around, you will see me in front of you."

Elvis Presley was deeply affected by Gibran's The Prophet after receiving his first copy in 1956. He reportedly read passages to his mother and over the years gave away copies of "The Prophet" to friends and colleagues. Photographs of his handwritten notes under certain passages throughout his copy are archived on various Museum websites. One of his most notable lines of poetry is from "Sand and Foam" (1926), which reads: "Half of what I say is meaningless, but I say it so that the other half may reach you". This line was used by John Lennon and placed, though in a slightly altered form, into the song "Julia" from The Beatles' 1968 album The Beatles (aka "The White Album"). Johnny Cash recorded Gibran's "The Eye of the Prophet" as an audio cassette book, and Cash can be heard talking about Gibran's work on a track called "Book Review" on his album Unearthed. British singer David Bowie mentioned Gibran in the song "The Width of a Circle" from Bowie's 1970 album The Man Who Sold the World. Bowie used Gibran as a "hip reference", because Gibran's work "A Tear and a Smile" became popular in the hippy counterculture of the 1960s. In 2016 Gibran's fable On Death was composed in Hebrew by Gilad Hochman to the unique setting of Soprano, theorbo and percussion and premiered in France under the title River of Silence.

Gibran's best-known work is The Prophet, a book composed of twenty-six poetic essays. Its popularity grew markedly during the 1960s with the American counterculture and then with the flowering of the New Age movements. It has remained popular with these and with the wider population to this day. Since it was first published in 1923, The Prophet has never been out of print. Having been translated into more than forty languages, it was one of the bestselling books of the twentieth century in the United States.

Gibran willed the contents of his studio to Mary Haskell. There she discovered her letters to him spanning twenty-three years. She initially agreed to burn them because of their intimacy, but recognizing their historical value she saved them. She gave them, along with his letters to her which she had also saved, to the University of North Carolina at Chapel Hill Library before she died in 1964. Excerpts of the over six hundred letters were published in "Beloved Prophet" in 1972.

His more than seven hundred images include portraits of his friends WB Yeats, Carl Jung and Auguste Rodin. A possible Gibran painting was the subject of a September 2008 episode of the PBS TV series History Detectives. His drawings were collected by Mathaf: Arab Museum of Modern Art in Doha.

Gibran had a number of strong connections to the Bahá'í Faith. One of Gibran's acquaintances later in life, Juliet Thompson, reported several anecdotes relating to Gibran. She recalled Gibran had met 'Abdu'l-Bahá, the leader of the religion at the time of his visit to the United States, c. 1911 – c. 1912. Gibran was unable to sleep the night before meeting him in person to draw his portrait. Thompson reported Gibran later saying that all the way through writing Jesus, the Son of Man, he thought of `Abdu'l-Bahá. Years later, after the death of `Abdu'l-Bahá, Gibran gave a talk on religion with Bahá'ís and at another event with a viewing of a movie of `Abdu'l-Bahá, Gibran rose to talk and proclaimed in tears an exalted station of `Abdu'l-Bahá and left the event weeping. A noted scholar on Gibran is Suheil Bushrui from Gibran's native Lebanon, also a Bahá'í, published more than one volume about him and served as the Kahlil Gibran Chair for Values and Peace at the University of Maryland and winner of the Juliet Hollister Awards from the Temple of Understanding.

Many of Gibran's writings deal with Christianity, especially on the topic of spiritual love. But his mysticism is a convergence of several different influences: Christianity, Islam, Judaism and Theosophy. He wrote: "You are my brother and I love you. I love you when you prostrate yourself in your mosque, and kneel in your church and pray in your synagogue. You and I are sons of one faith—the Spirit."