Despite its escape in 1633, the church was one of the first buildings to be destroyed in the Great Fire of London in 1666. St Magnus stood less than 300 yards from the bakehouse of Thomas Farriner in Pudding Lane where the fire started. Farriner, a former churchwarden of St Magnus, was buried in the middle aisle of the church on 11 December 1670, perhaps within a temporary structure erected for holding services.
The parish engaged the master mason George Dowdeswell to start the work of rebuilding in 1668. The work was carried forward between 1671 and 1687 under the direction of Sir Christopher Wren, the body of the church being substantially complete by 1676. At a cost of £9,579 19s 10d St Magnus was one of Wren's most expensive churches. The church of St Margaret New Fish Street was not rebuilt after the fire and its parish was united to that of St Magnus.
The chancels of many of Wren’s city churches had chequered marble floors and the chancel of St Magnus is an example, the parish agreeing after some debate to place the communion table on a marble ascent with steps and to commission altar rails of Sussex wrought iron. The nave and aisles are paved with freestone flags. A steeple, closely modelled on one built between 1614 and 1624 by François d'Aguilon and Pieter Huyssens for the church of St Carolus Borromeus in Antwerp, was added between 1703 and 1706. London's skyline was transformed by Wren's tall steeples and that of St Magnus is considered to be one his finest.
The large clock projecting from the tower was a well-known landmark in the city as it hung over the roadway of Old London Bridge. It was presented to the church in 1709 by Sir Charles Duncombe (Alderman for the Ward of Bridge Within and, in 1708/09, Lord Mayor of London). Tradition says "that it was erected in consequence of a vow made by the donor, who, in the earlier part of his life, had once to wait a considerable time in a cart upon London Bridge, without being able to learn the hour, when he made a promise, that if he ever became successful in the world, he would give to that Church a public clock ... that all passengers might see the time of day." The maker was Langley Bradley, a clockmaker in Fenchurch Street, who had worked for Wren on many other projects, including the clock for the new St Paul's Cathedral. The sword rest in the church, designed to hold the Lord Mayor's sword and mace when he attended divine service "in state", dates from 1708.
Duncombe and his benefactions to St Magnus feature prominently in Daniel Defoe's The True-Born Englishman, a biting satire on critics of William III that went through several editions from 1700 (the year in which Duncombe was elected Sheriff).
Shortly before his death in 1711, Duncombe commissioned an organ for the church, the first to have a swell-box, by Abraham Jordan (father and son). The Spectator announced that "Whereas Mr Abraham Jordan, senior and junior, have, with their own hands, joinery excepted, made and erected a very large organ in St Magnus' Church, at the foot of London Bridge, consisting of four sets of keys, one of which is adapted to the art of emitting sounds by swelling notes, which never was in any organ before; this instrument will be publicly opened on Sunday next [14 February 1712], the performance by Mr John Robinson. The above-said Abraham Jordan gives notice to all masters and performers, that he will attend every day next week at the said Church, to accommodate all those gentlemen who shall have a curiosity to hear it".
The organ case, which remains in its original state, is looked upon as one of the finest existing examples of the Grinling Gibbons's school of wood carving. The first organist of St Magnus was John Robinson (1682–1762), who served in that role for fifty years and in addition as organist of Westminster Abbey from 1727. Other organists have included the blind organist George Warne (1792–1868, organist 1820-26 until his appointment to the Temple Church), James Coward (1824–80, organist 1868-80 who was also organist to the Crystal Palace and renowned for his powers of improvisation) and George Frederick Smith FRCO (1856–1918, organist 1880-1918 and Professor of Music at the Guildhall School of Music). The organ has been restored several times - in 1760, 1782, 1804, 1855, 1861, 1879, 1891, 1924, 1949 after wartime damage and 1997 - since it was first built. Sir Peter Maxwell Davies was one of several patrons of the organ appeal in the mid-1990s and John Scott gave an inaugural recital on 20 May 1998 following the completion of that restoration. The instrument has an Historic Organ Certificate and full details are recorded in the National Pipe Organ Register.
The hymn tune "St Magnus", usually sung at Ascensiontide to the text "The head that once was crowned with thorns", was written by Jeremiah Clarke in 1701 and named for the church.