The site goes back further than the building. A church called Blagbourne is recorded here in 596 AD, in the early Christian missions to Anglo-Saxon Northumbria, which would make it one of the older Christian sites in northern England. A stone Norman church stood here after the Conquest. By the late eighteenth century the medieval church was old, the building was small for the booming cotton town spreading around it, and the parish demolished it in 1819 and 1820. John Palmer, a Lancaster architect, was commissioned to build the replacement in 1826: a clean Greek Revival nave with Gothic detailing, the kind of dignified market-town parish church Lancashire built by the dozen during the cotton boom.

Palmer's church was a parish church for exactly one century. In 1926 the Diocese of Manchester was split, and the new Diocese of Blackburn needed a cathedral. Rather than building one, the diocese simply raised St Mary's to cathedral status. The Georgian nave became the cathedral nave, and the chapter began fundraising for the extensions a proper cathedral was supposed to have. By 1938 there was enough money to start. Work on the new east end began. Then the Second World War broke out, and Lancashire's cathedral builders, like most of the country's construction industry, stopped. Work resumed in the 1950s. The architect W. A. Forsyth died in 1950 and was succeeded by Laurence King, who designed the lantern tower that became the cathedral's signature.

King's lantern tower was completed in 1967 and the cathedral itself was finished in 1977, more than thirty years after Forsyth's first stones went down. The tower's modernism, the aluminium spire and the panels of coloured glass that wash the interior with shifting light, sat oddly with Palmer's restrained Greek Revival nave. Many cathedral additions over the centuries do. By 1998 the concrete of the original 1960s tower was failing and it was rebuilt in natural stone, with the glass panels replaced. The east end roofs and parapets were rebuilt between 2000 and 2001. Mark Jalland's sculpture The Healing of the Nations, an abstract circular piece in steel and copper threaded with thousands of optical fibres that change colour at night, was installed on the exterior the same year. The cathedral was, after seventy years of construction, finally considered finished.

Eight fifteenth-century misericords sit in the north transept. They almost certainly came from Whalley Abbey, fifteen miles to the north-east, which was suppressed in the Dissolution of 1537. Where they were for the three hundred years between Whalley's suppression and Blackburn's nineteenth-century rebuild is unclear. They may have sat in a Lancashire builder's yard. They may have been kept in a private chapel. What is certain is that they survived, with their carved hidden faces and hinged seats designed to give monks somewhere to perch during long offices while still appearing to stand. Old wood with grim humour carved underneath, the misericords are quietly the oldest thing in the building.

Elizabeth II made her first visit to the cathedral on 17 April 2014 for the Royal Maundy service, distributing Maundy coins to 88 men and 88 women in keeping with her age that year. The cathedral has shared a chapel with a Welsh Presbyterian congregation since 2023, a first-of-its-kind covenant between a cathedral and a non-Anglican denomination. During the COVID-19 pandemic in 2021, the crypt became one of the borough's largest public vaccination centres. The cathedral choir still sings the parish communion on Sundays, and the organ designed by Aristide Cavaillé-Coll in the 1870s still plays. The flagpole carved by Mark Bridges in 2009 is topped by a bishop's mitre painted in gold leaf with the Red Rose of Lancaster. Almost nothing about the building is original. Almost everything about it is Lancastrian.