"Ultimo" was originally the name of the estate of Dr John Harris, on 14 hectares (34 acres) granted to him by Governor King in 1803, for his military service and for aiding the governor in curtailing the illegal trading of rum by a corrupt group in the NSW Corps (the Rum Corps).

At that time, most of the current streets were laid out, and the descendants of John Harris constructed the first residences in the area (at least one of which–a row of terraces in Wattle Street–was still owned by the family in the early 1980s).

However, the construction of factories, quarries, woolstores and a power station in the early 20th century saw the demolition of hundreds of houses, and a steady decline in population.

In 1973, the Builders Labourers Federation organised a green ban with Pyrmont to stop the construction of the North Western Expressway, which would've destroyed large parts of both suburbs.

By the start of the 1980s, derelict industrial sites began to be redeveloped for residences, mostly as apartments, a process that continues to the present.

One conspicuous industrial relic is the brick shell of Davey's Flour Mill, built in 1911, and adjacent to the southern approach to the Anzac Bridge.

The Dairy Farmer's Cooperative operated from its facility in Harris Street and Ultimo Road from 1912 to its closure in 2009, after which the site was redeveloped by the nearby UTS in a project designed by architect Frank Gehry.

Ultimo has a number of heritage-listed sites, including: One of the landmarks in the area is the Uniting Church on the corner of Quarry Street and Bulwara Road.

The Broadway Shopping Centre is located in the former site of the flagship building of the Grace Bros department store chain.

The Ultimo area is undergoing gentrification, with considerable redevelopment of industrial buildings for residential and commercial purposes.

The NSW transmission network service provider TransGrid is located on Thomas Street.

The Inner West Light Rail has stations at the eastern edge of the suburb, where Ultimo borders Darling Harbour.

A distinctive landmark in Ultimo is the former railway viaduct that now carries the light rail through Wentworth Park.

Despite slum clearance and redevelopment during the 20th century, many fine examples exist which, as in other inner Sydney suburbs, have been progressively 'gentrified' in recent times.

Barnardos Early Learning Centre is accessible from the Jones Street side of the property, with its balcony overlooking Ultimo Public School to the west.