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The church was rebuilt by the Commission for Building Fifty New Churches. Work began in 1716 and the new church was reopened for worship on Easter Day 1727. It was commissioned from Nicholas Hawksmoor, who had responded with one of his most distinctive and original designs. He benefited greatly from having an unusually open area in which to work. The old church had been hemmed in by shops and houses, like many other City churches, but these were demolished at the same time as the church. Hawksmoor was thus able to fully exploit the unobstructed front of the site. St Mary Woolnoth is Hawksmoor's only City of London church.

The resultant church was something of an architectural statement on Hawksmoor's part. Its unusually imposing façade, in English Baroque style, is dominated by two flat-topped turrets supported by columns of the Corinthian order, which are used throughout the church. The west side of the façade, facing Lombard Street, has distinctive recesses bearing an inset forward-curving pediment resting on skewed columns. The church underwent major changes in the late 19th century and the turn of the 20th century; it was proposed for demolition on several occasions but was saved each time. Its galleries were removed by William Butterfield in 1876, who thought they were unsafe, and a number of other significant (and not entirely successful) changes were made at the same time.

Between 1897 and 1900 the City & South London Railway (C&SLR) built Bank Underground station beneath the church. The C&SLR were given permission to demolish it, but public outcry forced them to reconsider: the company undertook to use only the subsoil instead. The crypt was sold to the railway and the bones were removed for reburial at Ilford. The walls and internal columns of the church were then supported on steel girders while the lift shafts and staircase shaft for Bank station were built directly beneath the church floor. At this time, the bells were also rehung with new fittings. No cracks formed in the plasterwork, and no settlement of the structure occurred; the company later claimed that the edifice of the church was considerably stronger than before.