Johnny Swet (former general manager of Bowery Bar, Balthazar, Pastis and Freeman’s); Larry Poston Jr. (formerly front-of-the-house manager at Town, Pastis and the Waverly Inn); Jonathan Hettinger (who had run a private-equity fund before managing Cafeteria in South Beach, Fla.); and Jesse Keyes (founding partner of La Esquina and Goldbar) were having trouble coming up with a name for their 3,600-square-foot venture between Fifth and Sixth avenues, the basement of three linked, landmarked, 19th-century Anglo-Italianate brownstones.

“Ocean’s 21” read the name on the broken-down awning—a Rat Pack–themed ’50s-style speakeasy that had been closed for four years. Before that it was the infamous Marylou’s, where Jack Nicholson and Robert De Niro were regulars and the drugs flowed as freely as the booze; before that, a steakhouse called Nat Simon’s Penguin. None of these inspired.

Then, after a meeting with the buildings’ co-op board in late January, Robyn Malin-Rubinstein, the board’s treasurer, asked whether the partners knew that the space had encompassed the Hotel and Restaurant Griffou in the late 1800s.

She told them the buildings were built in 1851 as a boardinghouse that Marie Griffou and her second husband took over in the early 1870s. In its heyday, muckraker Ida Tarbell had lived at the hotel and frequented the restaurant, a writers’ hangout. It was referred to in at least three novels by two Gilded Age customers (Thomas A. Janvier’s At the Casa Napoleon, and William Dean Howell’s The World of Chance and A Hazard of New Fortunes). Someone, Ms. Malin-Rubinstein added, had kept a brown bear tied up in the backyard before the authorities required its removal to the Central Park Zoo.

The partners went into a research frenzy.

They found that Mark Twain dined at the Griffou. Oscar Wilde did, too, during his 1882 American tour. The baby bear was apparently purchased by Louis Napoleon Griffou, Madame Griffou’s son, who, it was said, feared the temptation to buy something foolish with his earnings.

Madame Griffou died in 1905, and her establishment made its last headlines a year later, when a 60-year-old married banker killed his 28-year-old lover and then himself in one of the hotel’s rooms. (Ms. Malin-Rubenstein, who has lived for the past decade in a spacious modern duplex on the third and fourth floors where she and her husband, Jason, the co-op president, run Product Lounge, a home design licensing firm, was a bit taken aback to discover that the very room in which the murder-suicide took place is one of the eight that make up her apartment.)

Sometime between that incident and 1907, the Hotel Griffou closed. By 1909, it had reopened as the Hotel Europe, according to the New York Times obituary for Xavier Hernandez, the Griffou’s maitre d’ for 35 years, who died that year in his room upstairs. In 1929, a new owner’s plan to demolish the buildings and rebuild was averted by the stock market crash. (No one has yet been able to fill in what went on in the three decades between the Depression and the 1960s, when it became the Penguin.)

The new Griffou is open now, in an age more tarnished than gilded, with a vodka-elderflower cocktail named the Tarbell on its retro-inflected menu. As celebrities like Chloë Sevigny, Rachel Roy, Harvey Weinstein, John Leguizamo and Ross Bleckner filter in, the partners are still finding the past a calming obsession. “It’s like ready-made soul,” said Mr. Swet, who is trying to establish historical proof that Edna St. Vincent Millay, his poet idol who once lived on the block, was a regular at the old Griffou. He’s still looking.