The construction of the current bridge occurred between 1473 and 1479, and was commissioned by Pope Sixtus IV (r. 1471–84), after whom it is named, from the architect Baccio Pontelli, who reused the foundations of a prior Roman bridge, the Pons Aurelius, which is also known as Pons Antoninus and had been destroyed during the early Middle Ages.

"[1] The Pons Antoninus was partially destroyed in 772, at the time the Lombard king Desiderius took Rome, and rebuilt in its current form by Pope Sixtus IV, whose name it carries to this day.

They recite: and On the corner of via dei Pettinari and via Giulia once stood a fountain (the Fontanone di Ponte Sisto or dei Cento Preti), which relayed water from the great fountain called the Acqua Paola, derived originally from a Roman aqueduct brought back to working order by Pope Paul V (r. 1605–21): the water was brought from Lake Bracciano to Trastevere and from there over the Ponte Sisto to the Campo Marzio.

After considerable controversies, Rome's mayor Francesco Rutelli let them be demolished in 2000, restoring Ponte Sisto's pristine silhouette, and since then traffic on the bridge has been restricted to pedestrians.

The Ponte Sisto connects the lively and popular Campo de' Fiori area (reached through via dei Pettinari) and via Giulia with Piazza Trilussa in Trastevere across the river, where many young Romans and tourists gather for an aperitivo on a Friday night.