The clubhouse cost about £165,950 to build — a substantial figure in the early 1880s — and Waterhouse blended French, Gothic, and Italianate elements into a Renaissance Revival composition heavy with Burmantofts Pottery tilework manufactured in Leeds by Wilcox and Co. The members of the new club, fascinated by the cutting edge of late-Victorian technology, insisted on bare electric light bulbs in their chandeliers because the distinctive hue of incandescent lighting was the modern marvel of the age. The Club had its own branch of the Post Office. It had a vast Gladstone Library, holding 35,000 volumes before its dispersal in 1977. It had two ballrooms. And, in one of the more curious facts of London's underground geography, its wine cellar was converted from a tunnel originally dug between 1865 and 1868 for the Waterloo and Whitehall Railway — a pneumatic line that was supposed to carry freight from Scotland Yard to Waterloo Station on compressed air, abandoned mid-project. When the railway company wound up in 1882, the new Club adapted its tunnel.

Through the late nineteenth and twentieth centuries the Club resided just slightly off-axis to the political mainstream — close enough to power to matter, far enough from it to attract eccentrics. David Lloyd George lived at the Club in the 1890s, when he was a young Liberal MP rather than a wartime Prime Minister. Cyril Smith lived here in the 1970s. Menzies Campbell in the late 1980s. Among writer-members were Rupert Brooke, G. K. Chesterton, Jerome K. Jerome, George Bernard Shaw, Bram Stoker, Dylan Thomas, H. G. Wells, and Leonard Woolf. Wells made the Club a setting in his autobiographical novel Tono-Bungay (1909). Chesterton put it into a short story. P. G. Wodehouse used it as shorthand for pandemonium: in one Mulliner tale, a scene of complete chaos is described as "more like that of Guest Night at the National Liberal Club than anything he had ever encountered."

By the 1980s the Club had a problem the founders never envisaged: too much building. The Liberal Party had decamped to the upper floors as its national headquarters between 1977 and 1988, but the Club itself struggled to fill 140 bedrooms across six floors. In 1985 it began a two-year negotiation to sell the second-floor and basement function rooms, the two vast ballrooms, the Gladstone Library, and the upper bedrooms to the Royal Horseguards Hotel next door — which is approached from a different entrance and has operated as a hotel since 1971. The sale was contested by some members but secured the Club's future. What remains — chiefly the ground and first floors — is still one of the largest clubhouses in the world, with facilities for around two thousand active members. The Annual Whitebait Supper still leaves Embankment Pier for the Trafalgar tavern in Greenwich, retracing the route Gladstone used to take his cabinet ministers by boat.

The Club had, from the start, allowed women in as visitors but barred them from membership. In 1967, a referendum approved a category of "Lady Associate Member," initially restricted to the wives and widows of male members, at a lower fee that bought lower privileges. The first five Lady Associates were approved in November 1967. Two years later, women not related to any male member could also be nominated, paying a different fee. The category included Violet Bonham Carter and the Liberal peer Nancy Seear. It took until 1976 for the Club to admit women as full members — making it the first major London club to do so, ahead of the Reform Club in 1981 and decades ahead of clubs that held out into the 1990s and 2000s. The first two full women members were Christina Baron and Joyce Arram. In 2016 the Club elected its first female chairman, Janet Berridge.

In 2002 Jeremy Paxman interviewed Liberal Democrat leader Charles Kennedy in the Smoking Room for Newsnight, and pressed him about his drinking — the first time a major television interviewer had raised the topic. In 2007 Nick Clegg launched his leadership campaign from the Club's David Lloyd George Room. The Liberal Democrat History Group meets here. Liberal International has had its international headquarters on the ground floor since 1977. The John Stuart Mill Institute lectures here. The Gladstone Club, founded in 1973 to discuss Liberal ideas, still meets. The Club is no longer the centre of British government, but it has held onto its purpose for a hundred and forty years longer than most institutions manage: a place where Liberals talk to other Liberals, and have done so without major interruption since Gladstone first walked through the doors.