By the 1250s a small stone chapel known as St Mary del Quay had been built (the first place of worship on the current site of the church).

By the late 15th century, a north aisle, the same size as the original nave, had been added, and three chantry altars had been established.

The building was adapted in stages to suit the form of worship found in the Book of Common Prayer.

St Peter's, which was situated in Church Street, was demolished in 1922, having served as pro-cathedral for the Anglican Diocese of Liverpool.

The last remains of the original chapel of St Mary del Quay, which had been used as a tavern, were demolished.

From 1758 to 1772, a battery of guns stood on an area of the burial ground (now covered by road) to defend the river.

Until 1767, when Georges Dock was built where the Liver Building now stands, the River Mersey reached the church garden walls at high tide.

In 1891 it was transformed into a public garden in memory of James Harrison, whose shipping company had its offices facing the churchyard until the early 21st century.

Following a German air raid on 21 December 1940, the main body of the church was destroyed by fire, leaving only the parish rooms, vestries and the 19th-century tower.

Unlike churches in which the pulpit is traditionally the most prominent feature, Butler emphasised the sanctuary.

The positions of the organ and Refectory were changed; situated above the Narthex (entrance vestibule), they reduced the seating space within the church.

The exterior of the church is notable for its distinctive lantern spire, which can be easily spotted from the river, despite being overshadowed by many taller buildings of the city's business district.

In the southeast corner of the church is a stained glass window: Our Lady stands in glory as in Revelation and St Nicholas holds a ship.

A war memorial for the Cunard Steamship Company, placed in the church in 1989, is in the north east corner.

The church organ is by Rushworth and Dreaper of Liverpool, and is dedicated to the memory of Charles W. Bridson, organist 1902–1949.

The chapel to the north was that of St George, commemorating the former, nearby church of that dedication demolished to make way for the Queen Victoria monument at the head of Castle Street.

In that year the Maritime Chapel of St Mary del Quay was dedicated as part of the celebrations for the 50th anniversary of the Battle of the Atlantic.

Behind the church's high altar is an icon of the crucifixion painted by the Romanian artist Tatiana Nichita, donated in commemoration of Merseyside Police Constable Neil Doyle, who was murdered in Liverpool city centre while off-duty, and whose funeral took place at the church.

A gilded copper weather vane in the form of the ship is on top of the tower of St Nicholas'.

Historic photos show ships as weather vanes on the Bluecoat Hospital and one of the Goree warehouses.