Gentile's earliest signed work is The Blessed Lorenzo Giustinian (1445), one of the oldest surviving oil paintings in Venice, (now at the Accademia Museum). During the 1470s Bellini worked on a commission for the Scuola Grande di San Marco and painted in conjunction with his brother, Giovanni Bellini. From 1474 he was also the official portrait artist for the Doges of Venice (e.g., image of the Doge Giovanni Mocenigo).

Much of Gentile Bellini’s surviving work consists of very large paintings for public buildings, including those for the Scuola Grande di San Giovanni Evangelista. Along with Lazzaro Bastiani, Vittore Carpaccio, Giovanni Mansueti and Benedetto Rusconi, Bellini was one of the artists hired to paint the 10 - painting narrative cycle known as The Miracles of the Relic of the Cross. The commission was intended to celebrate the relic of the Holy Cross which the confraternity had received in 1369. Gentile's contributions are among his best known works today, especially the Procession of the True Cross in Piazza San Marco (now in the Accademia, Venice), which dates from 1496.

The canvas shows an event that took place about 50 years earlier, in 1444: while the members of the Scuola were processing the fragment through the Piazza San Marco (the square of St. Mark’s), a man from Brescia knelt before the relic in prayer that his dying son might recover. When he returned home, he discovered that the boy was completely well again. In the foreground, Gentile has painted the confraternity in its white robes, processing at the head of the parade, the large golden reliquary suspended between them, carried beneath a canopy held by four more Scuola members. Although the subject of the picture is ostensibly the miracle itself, the Brescian merchant is hardly visible in the crowd: he kneels in sumptuous red robes, immediately to the right of the last two canopy - bearers. Rather, the subject of the picture might be more accurately described as the procession, with a special focus on the space of St. Mark’s square and on St Mark's Basilica itself, with its Byzantine domes and glittering mosaics.

Another very well known Gentile canvas is also from this cycle: The Recovery of the Relic of the True Cross at the Bridge of S. Lorenzo, which dates from c.1500. The Recovery offers a similar snapshot of Venetian life at the time, concentrating as much on human individuality and aspects of daily life, as on the event of the miracle.

Venice was, at that time, a very important point in which cultures and trade bordered on the eastern Mediterranean Sea and provided gateways to Asia, Africa, and beyond. As noted, in his lifetime, Gentile was the most prestigious painter in Venice. Therefore in 1479, he was chosen by the government of Venice to work for Sultan Mehmed II in Constantinople. However in addition to his work at the Ottoman Court, Gentile's work also responded to other aspects of the East, including the Byzantine Empire.

In September 1479 Gentile was sent by the Venetian Senate to the new Ottoman capital Constantinople as part of the peace settlement between Venice and the Turks. His role was not only as a visiting painter in an exotic locale, but also as a cultural ambassador for Venice. This was important to Mehmed II, as he was particularly interested in the art and culture of Italy, and he attempted on several occasions to have himself portrayed by Italian artists. He finally reached his goal with Gentile, who is believed to have painted the portrait of Mehmed II now in the National Gallery, London, (but largely overpainted). It has been noticed that the portrait is like one of the figures in a painting by Marco Palmezzano, Jesus among the Doctors in the Temple (Brisighella, near Forlì and Ravenna). So the dating and authorship of the portrait by Bellini have been placed in question.

Subsequently an Oriental flavour appears in several of his paintings, including the portrait of a Turkish artist and St. Mark Preaching at Alexandria. The last was completed by his brother, Giovanni Bellini.

Gentile responded to other aspects of the East, including the Byzantine Greek Empire, as well as Venice’s other trading partners in North Africa and Levant. Venice had a long established relationship with the Eastern Mediterranean. Saint Mark, Venice’s patron, was from the Egyptian city of Alexandria, and Venice’s cultural and spiritual centre – the basilica of San Marco – was built in his honor (and as his mausoleum) in the Greek Byzantine style. Although Constantinople fell to the Ottoman Turks in 1453, the Greek Byzantine world had a continuing impact upon Venetian art and culture as a number of Greek Christians fled Muslim rule. It was here that Gentile painted the portrait of Queen Caterina Cornaro of Cyprus. This is counted as the second known portrait including the queen, which is now in the collection of the Szepmuveszeti Museum in Budapest.

Bellini's most important paintings, the monumental canvases in the Doge’s Palace in Venice, were destroyed by fire in 1577. Only a few of his other works remain, namely the large narrative paintings The Procession in Piazza San Marco and The Preaching of Saint Mark in Alexandria, produced in his final years. Little remains of Gentile’s art from the 1470s and 1480s, except for the works made in Constantinople. Moreover, many workshop paintings and drawings have been assigned to Gentile Bellini. This has had the unfortunate consequence of confirming his reputation as an awkward artist, especially in comparison with his beloved brother Giovanni. Gentile's fall from popular favor seems to have begun shortly after his death; by 1557 Lodovico Dolce made a rather acerbic comment about him as an early teacher of Titian:

Titian could not bear to follow the dry and labored manner of Gentile... Because of this, leaving this awkward Gentile, Titian attached himself to Giovanni Bellini: but his style did not entirely please him either, and he sought out Giorgione.

He was interred in the Basilica di San Giovanni e Paolo, a traditional burial place of the doges.

In recent years, Gentile has once again generated interest, especially in a recent spate of scholarly publications and exhibitions on the subject of cross - cultural exchange between Europe and the Levant.