By age 12 years, he apprenticed with Angelo Michele Toni (1640-1708). From the age of 15-18 years, he worked under the Bolognese Domenico Maria Canuti. The Roman painter Carlo Maratti, on a visit to Bologna, is said to have invited Crespi to work in Rome, but Crespi declined. Maratti's friend, the Bolognese Carlo Cignani invited Crespi in 1681-1682 to join an Accademia del Nudo for the purpose of studying drawing, and he remained in that studio until 1686, when Cignani relocated to Forlì and his studio was taken over by Canuti's most prominent pupil, Giovanni Antonio Burrini. From this time hence, Crespi worked independently of other artists.
His main biographer, Giampietro Zanotti, said of Crespi: (He) "never again wanted for money, and he would make the stories and caprices that came into his imagination. Very often also he painted common things, representing the lowest occupations, and people who, born poor, must sustain themselves in serving the requirements of wealthy citizens". Thus it was for Crespi himself, as he began a career servicing wealthy patrons with artwork. He is said to have had a camera optica in his house for painting. By the 1690s he had completed various altarpieces, including a Temptation of Saint Anthony commissioned by Count Carlo Cesare Malvasia, now in San Niccolò degli Albari.
He journeyed to Venice, but surprisingly, never to Rome. Bearing his large religious canvas of Massacre of the Innocents and a note from Count Vincenzo Rannuzi Cospi as an introduction, Crespi fled in the middle of the night to Florence in 1708, and gained the patronage of the Grand Duke Ferdinand I de' Medici. He had been forced to flee Bologna with the canvas, which while intended for the Duke, had been fancied by a local priest, Don Carlo Silva for himself. The events surrounding this episode became the source of much litigation, in which Crespi, at least for the next five years, found the Duke a firm protector.
An eclectic artist, Crespi was a portrait painter and a brilliant caricaturist, and was also known for his etchings after Rembrandt and Salvator Rosa. He could be said to have painted a number of masterpieces in different styles. He painted few frescoes, in part because he refused to paint for quadraturists, though in all likelihood, his style would not have matched the requirements of a medium then often used for grandiloquent scenography. He was not universally appreciated, Lanzi quotes Mengs as lamenting that the Bolognese school should close with the capricious Crespi. Lanzi himself describes Crespi as allowing his turn for novelty at length to lead his fine genius astray. He found Crespi included caricature in even scriptural or heroic subjects, he cramped his figures, he fell in to mannerism, and painted with few colors and few brushstrokes,employed indeed with judgement but too superficial and without strength of body .
One celebrated series of canvases, the Seven Sacraments, was painted around 1712, and now hangs in the Gemäldegalerie, Dresden. It was originally completed for Cardinal Pietro Ottoboni in Rome, and upon his death passed to the Elector of Saxony. These imposing works are painted with a loose brushstroke, but still maintain a sober piety. Making no use of hieratic symbols such as saints and putti, they utilize commonplace folk to illustrate sacramental activity.
True to his eclecticism is the naturalistic Saint John Nepomunk confessing the Queen of Swabia, made late in life. In this painting, much is said by partially shielded faces. His Resurrection of Christ is a dramatic arrangement in dynamic perspectives, somewhat influenced by Annibale Carracci's altarpiece of the same subject.
While many came to work in the studio Crespi established after Cignani's departure, few became notable. Antonio Gionima was moderately successful. Others included Giovanni Francesco Braccioli, Giacomo Pavia, Giovanni Morini, Pier Guariente, and Cristoforo Terzi. He may also have influenced Giovanni Domenico Ferretti. While the Venetian Giovanni Battista Piazzetta claimed to have studied under Crespi, the documentation for this is nonexistent.
Two of Crespi's sons, Antonio (1712-1781) and Luigi (1708-1779) became painters. According to their account, Crespi may have used a camera obscura to aid in depiction of outdoor scenes in his later years. After his wife's death, he became reclusive, rarely leaving the house except to go to daily mass.
He painted many kitchen scenes and other domestic subjects. The painting of The Flea (1709-10) depicts a young woman readying for sleep and supposedly grooming for a nagging pest on her person. The environs are squalid—nearby are a vase with a few flowers and a cheap bead necklace dangling on the wall—but she is sheltered in a tender womb of light. She is not a Botticellian beauty, but a mortal, her lapdog asleep on the bed-sheets.
In another genre scene, Crespi captures the anger of a woman at a man publicly urinating on wall, with a picaresque cat also objecting to the man's indiscretion.