The pub in itself is one of the oldest in London, having first been built in 1415 in what was then the rural village of Islington in open countryside and fields. A house called Goose Farm and some nearby cattle pens (for herds being driven to Smithfield Market) were the only structures to adjoin it, and St John Street (then called Chester Road) was a country lane.
In the late 18th century Chester Road became notorious for highwaymen, with patrols being provided to protect those travelling along it at night. At this time descriptions state that the Old Red Lion was a small brick house with three trees in its forecourt, visited by William Hogarth (who portrayed it in the middle distance of his painting "Evening", with the foreground being Sadler's Wells), Samuel Johnson and Thomas Paine (who wrote The Rights of Man in the shade of the trees in its forecourt).
The Old Red Lion was rebuilt in 1899, designed by Eedle and Myers for Charles Dickerson and John William North, adding two exits onto different streets. This gave the pub the nickname "the In and Out", since taxi passengers could avoid paying their fare by entering it through one door and disappearing through the other. The architectural style is Free-Classical style, but includes Neo-Jacobean and Renaissance elements. The building is four storeys high, with residential accommodation in the floors above the pub. The parapet is balustraded with a name panel inscribed with lettering in Arts and Crafts style: "THE OLD RED LION 1415 REBVILT 1899". The pub retains several identical pairs of original glazed doors with glazing, wrought iron wall lanterns on pillars, and much of its original interior.
In 1979 the pub became a family-run pub theatre, run by the Devine family. A small studio theatre opened on the pub's first floor as the Old Red Lion Theatre Club. Under artistic director Charlie Hanson, it became a place for actors, directors, designers, writers, and technicians to experiment. After the King's Cross fire in 1987, the theatre was threatened with closure due to the tightening of fire regulations. Artistic director Ken McClymont raised funds to install a fire escape, to keep the theatre from closing.