Jamalzadeh's father, Sayyed Jamal ad-Din Esfahani, was a progressive mullah and preacher who became a constitutional revolutionary, delivering raging sermons which inspired his son but cost him his life; he was executed in 1908 on the order of Mohammad-Ali Shah Qajar who considered him among the most dangerous of his enemies. The young Jamalzadeh lived in Iran only until he was twelve or thirteen. Thereafter, he lived in Lebanon, where he attended the Aintoura Catholic School (1908) near Beirut, in France (1910), and in Switzerland where he read law at University of Lausanne and later at University of Burgundy in Dijon, France.
After his father's death, Jamalzadeh's life took a turn for the worse, but thanks to many supporting friends and to occasional paid teaching jobs, he survived starvation. By the time of the World War I, still in his early age, he joined a group of Iranian nationalists in Berlin and, in 1915, founded a newspaper (Rastakhiz) for this group in Baghdad. During this time he also worked for the periodical Kāveh (1916). In 1917, he published his first book Ganj-e Shaye-gan (The Worthy Treasure). An overview of Iran of the turn of the century, Ganj-e Shaye-gan deals with Iran's socio-political and economic problems, a major contribution which bridges the gap between literature and science. In the same year he represented the Nationalists at the World Congress of Socialists in Stockholm. His later years, until 1931 when he settled in Geneva and worked thereafter for the International Labour Organization, were spent in temporary employments, such as one at the Iranian embassy in Berlin.
During all these years, Jamalzadeh had very little contact with Iran. But that did not bar him from learning Persian on his own. Drawing on his scant experiences gained at a young age, he wrote about the lives of contemporary Iranians. His preoccupation with the use of language and his Dickensian style of writing, including repetitions, piling up of adjectives, and using popular phrases, quickly remind the reader of Jamalzadeh's background and of his sincere intentions. However, his physical distance from the scenes of the events described in his stories somewhat compromises the accuracy of his works.
Jamalzadeh's major work Yeki Bud Yeki Nabud (یکی بود یکی نبود - Once Upon a Time), published in 1921 in Berlin, did not reach Iran until a year later, and when it did, it was not received favourably. The public, especially the clergy, loathed Jamalzadeh's portrayal of their country to the degree that copies of the book were burned in public squares. A collection of six short stories, Yeki Bud Yeki Nabud deals with the social and political conditions in Iran at the turn of the century, a subject that up to then had been outside the purview of writers and poets in general. Moreover, interwoven with this is a considerable amount of militancy against Western interference in Iran and an open mockery of religious fanaticism. Jamalzadeh's simple and colloquial style, combined with a measured humour, enhanced the impact of his writings, making his stories such as Yeki Bud Yeki Nabud and Farsi Shekar ist (Persian is Sugar) even more poignant than otherwise would be the case.
This hostile public reaction affected Jamalzadeh to the degree that for the next twenty years he refrained from engaging in any literary activities. He began writing again in the 1940s, but by that time he had lost the dexterity that imparted conciseness, novelty of form, originality of ideas, a biting sense of humor, and a tight structure to his earlier stories. Tautologism, a tendency toward using sage remarks, making mystical and philosophical speculations, and disregard for order became the hallmark of his later writings. Sahra-ye Mahshar (Armageddon) (1947), Talkh-o Shirin (Bitter and Sweet) (1955), Kohne va Now (Old and New) (1959), Qair az Khoda Hichkas Nabud (None Existed Except God) (1961), Asman-o Risman (The Blue Yonder and Rope) (1965), Qesse-ha-ye Kutah Bara-ye Bachcheha-ye Rish-dar (Short Stories for Bearded Children [i.e. for Adults]) (1974), and Qesse-ye Ma be Akhar Rasid (Thus Ends Our Story) (1979) were written during this phase of his literary activity. Although Jamalzadeh continued to criticise the court and the clergy, some of his works of this period lack his original unique Persian style, even though he is at times as biting and as veracious as in his earlier writings.
After the 1979 Islamic Revolution, Jamalzadeh returned to Iran. To the surprise of many, he supported the changes brought about by Ayatollah Khomeini and praised the clergy in numerous public interviews.
Jamalzadeh died at the of age 105 in Geneva, Switzerland.