While his exact birthdate is unknown, it is believed that Silesius was born in December 1624 in Breslau, the capital of Silesia. The earliest mention of him is the registration of his baptism on Christmas Day, 25 December 1624. At the time, Silesia was a German-speaking province of the Habsburg Empire. Today, it is the southwestern region of Poland. Baptized Johann Scheffler, he was the first of three children. His parents, who married in February 1624, were Lutheran Protestants. His father, Stanislaus Scheffler (c. 1562–1637), was of Polish ancestry and was a member of the lower nobility. Stanislaus dedicated his life to the military, was made Lord of Borowice (or Vorwicze) and received a knighthood from King Sigismund III. A few years before his son's birth, he had retired from military Service in Kraków. In 1624, he was 62. The child's mother, Maria Hennemann (c. 1600–1639), was a 24-year-old daughter of a local physician with ties to the Habsburg Imperial court.

He subsequently studied Medicine and science at the University of Strasbourg (or Strassburg) in Alsace for a year in 1643. It was a Lutheran university with a course of study that embraced Renaissance humanism. From 1644 to 1647, he attended Leiden University. At this time, he was introduced to the writings of Jacob Böhme (1575–1624) and became acquainted with one of Böhme's friends, Abraham von Franckenberg (1593–1652), who probably introduced him to ancient Kabbalist writings, alchemy, and hermeticism, and to mystic Writers living in Amsterdam. Franckenberg had been compiling a complete edition of Böhme's work at the time Scheffler resided in the Netherlands. The Dutch Republic provided refuge to many religious sects, Mystics, and scholars who were persecuted elsewhere in Europe. Scheffler then went to Italy and enrolled in studies at the University of Padua in Padua in September 1647. A year later, he received a doctoral degree in philosophy and Medicine and returned to his homeland.

On 3 November 1649, Scheffler was appointed to be the court physician to Silvius I Nimrod, Duke of Württemberg-Oels (1622–1664) and was given an annual salary of 175 thalers. Although he was "recommended to the Duke on account of his good qualities and his experience in Medicine," it is likely that Scheffler's friend and mentor, Abraham von Franckenberg, had arranged the appointment given his closeness to the Duke. Franckenberg was the son of a minor noble from the village of Ludwigsdorf near Oels within the duchy. Franckenberg returned to the region the year before. It is also possible that Scheffler's brother-in-law, Tobias Brückner, who was also a physician to the Duke of Württemberg-Oels, may have recommended him. Scheffler soon was not happy in his position as his personal mysticism and critical views on Lutheran doctrine (especially his disagreements with the Augsburg Confession) caused friction with the Duke and members of the ducal court. The Duke was characterized in history as being "a zealous Lutheran and very bigoted." Coincidentally, it was at this time that Scheffler began to have mystical visions, which along with his public pronouncements led local Lutheran clergy to consider him a heretic. After Franckenberg's death in June 1652, Scheffler resigned his position—he may have been forced to resign—and sought refuge under the protection of the Roman Catholic Church.

In the late 1650s, he sought permission (a nihil obstat or imprimatur) from Catholic authorities in Vienna and Breslau to begin publishing his poetry. He had begun writing poetry at an early age, publishing a few occasional pieces when a schoolboy in 1641 and 1642. He attempted to publish poetry while working for the Duke of Württemberg-Oels, but was refused permission by the Duke's orthodox Lutheran court clergyman, Christoph Freitag. However, in 1657, after obtaining the approval of the Catholic Church, two collections of his poems were published—the works for which he is known—Heilige Seelenlust ("The Soul's Holy Desire") and Der Cherubinische Wandersmann ("The Cherubinic Pilgrim").

The Lutheran authorities in the Reformed states of the Empire were not tolerant of Scheffler's increasing mysticism, and he was publicly attacked and denounced as a heretic. At this time, the Habsburg rulers (who were Catholic) were pushing for a Counter Reformation and advocated a re-Catholicisation of Europe. Scheffler sought to convert to Catholicism and was received by the Church of Saint Matthias in Breslau on 12 June 1653. Upon being received, he took the name Angelus, the Latin form of "angel", derived from the Greek ángelos (ἄγγελος, "messenger"); for his epithet, he took Silesius (Latin for "Silesian"). It is uncertain why he took this name, but he may have added it in honour of his native Silesia or to honor a favourite scholastic, mystic or theosophic author, to distinguish himself from other famous Writers of his era: perhaps the Spanish mystic Writer Juan de los Ángeles (author of The Triumph of Love) or Lutheran theologian Johann Angelus in Darmstadt. He no longer used the name Scheffler, but did on occasion use his first name, Johann. From 1653 until his death, he used the names Angelus Silesius and also Johann Angelus Silesius.

Shortly after his conversion, on 24 March 1654, Silesius received an appointment as Imperial Court Physician to Ferdinand III, the Holy Roman Emperor. However, this was probably an honorary position to offer some official protection against Lutheran attackers, as Silesius never went to Vienna to serve the Imperial Court. It is very likely that he never practiced Medicine after his conversion to Catholicism.

The line he quoted, Die Rose ist ohne warum; sie blühet, weil sie blühet... from Silesius's The Cherubinic Pilgrim (1657), can be translated as: "The Rose is without a 'wherefor'—she blooms because she blooms." The influence of mysticism is seen in the work of Borges, especially in his poetry, which frequently references Silesius and his work.

On 27 February 1661, Silesius took holy orders as a Franciscan. Three months later, he was ordained a priest in the Silesian Duchy of Neisse—an area of successful re-Catholicisation and one of two ecclesiastical states within the region (that is, ruled by a Prince-Bishop). When his friend Sebastian von Rostock (1607–1671) became Prince-Bishop of Breslau, Silesius was appointed his Rath und Hofmarschall (a counselor and Chamberlain). During this time, he began publishing over fifty tracts attacking Lutheranism and the Protestant Reformation. Thirty-nine of these essays he later compiled into a two-volume folio collection entitled Ecclesiologia (1676).

Several of the poems of Silesius have been used or adapted as hymns used in Protestant and Catholic services. In many early Lutheran and Protestant hymnals, these lyrics were attributed to "anonymous", rather than admit they were penned by the Catholic Silesius, known for his criticism and advocacy against Protestantism. In many instances, the verse of Silesius is attributed in print to "anonymous" or to "I.A." While I.A. were the Latin initials for Iohannis Angelus they were often misinterpreted as Incerti auctoris, meaning "unknown author". Likewise, several truly anonymous works were later misattributed to Silesius, thanks to the same ambiguous initials. Verses by Silesius appear in the lyrics of hymns published in Nürnberg Gesang-Buch (1676), Freylinghausen's Gesang-Buch (1704), Porst's Gesang-Buch (1713); and Burg's Gesang-Buch (1746). Seventy-nine hymns using his verses were included in Nicolaus Zinzendorf's Christ-Catholisches Singe und Bet-Büchlein (1727). During the 18th Century, they were frequently in use in the Lutheran, Catholic, and Moravian Churches. Many of these hymns are still popular in Christian churches today.

After the death of the Prince-Bishop of Breslau in 1671, Silesius retired to the Hospice of the Knights of the Cross with the Red Star (the Matthiasstift), a Jesuit house associated with the church of Saint Matthias at Breslau. He died on 9 July 1677 and was buried there. Some sources claim he died from tuberculosis ("consumption"), others describe his illness as a "wasting sickness." Immediately after news of his death spread, several of his Protestant detractors spread the untrue rumor that Silesius had hanged himself. By his Will, he distributed his fortune, largely inherited from his father's noble estate, to pious and charitable institutions, including orphanages.

This same line was often referenced in the work of Martin Heidegger (1889–1976) who (building on the work of Leibniz and Hegel) explored mysticism in many of his works, in which he defines a theory of truth as phenomenal and defying any rational explanation. Heidegger was commenting on the rational philosophy of German Philosopher and Mathematician Leibniz (1646–1716)—a contemporary of Silesius—who called the mystic's poetry "beautiful", but "extraordinarily daring, full of difficult metaphors and inclined almost to godlessness" despite Silesius's mysticism being contrary to Leibniz's principium reddendae rationis sufficientis, the Principle of sufficient reason.

In a series of lectures entitled Siete Noches ("Seven Nights") (1980), Argentine Writer and poet Jorge Luis Borges (1899–1986) remarks that the essence of poetry can be encapsulated in a single line from Silesius. Borges wrote:

In the 1991 American film Cape Fear directed by Martin Scorsese, Max Cady (played by Robert De Niro) quotes a verse of Silesius. The verse is:

However, the context of this line in the film does not match the context intended by Silesius. The character of Cady uses it to emphasize dramatically to his intended victims the power of his individual will and his god-like ability to exact a violent vengeance. The context intended by Silesius was of man's realization through his spiritual potential for perfection that he was of the same substance with God in the sense of the mystical Divine union or theosis—that experience of direct communion of love between the believer and God as equals.