Start with what your days look like
This choice isn't about which neighborhood is better. It's about where your trip's center of gravity sits. If you wrote down the six things you want to do in New York and four of them are above 59th Street or in Midtown, the Upper East Side wins on math alone. If four of them are dinners, records, vintage shops and a bar you saw on Instagram, Williamsburg wins the same way.
We host on East 62nd Street, so treat this as a read from one side of the river. We'll be straight about where Williamsburg is the better call.
The commute is the real difference
Williamsburg has one great subway line and not much else. The L from Bedford Av reaches 14th Street-Union Square in about five minutes, which is genuinely fast, and Union Square connects to plenty. But the L only runs across 14th Street. Anything north of that, the Met, the Guggenheim, Central Park, Lincoln Center, Grand Central, means the L plus a transfer, and you're looking at 45 minutes to an hour each way. Do that twice a day for four days and you've spent most of a day underground.
From the East 60s, Midtown is one stop. The Q from Lexington Av/63 St gets to 57th Street in a couple of minutes and Times Square in about ten. The 4, 5 and 6 run down Lexington to Grand Central and Wall Street. Central Park is an eight-minute walk through the quiet blocks. Going the other direction, Williamsburg is a transfer away, roughly 40 minutes, which is fine for a dinner and a night out but not something you'd want to do four times.
Evenings
Williamsburg is better at night, and it isn't close. Bedford Avenue and the blocks around it run late, the restaurants take walk-ins later than most of Manhattan, and the waterfront at Domino Park with the Manhattan skyline across the water is one of the best free things in the city. Smorgasburg sets up in Williamsburg on Saturdays in the warm months.
The Upper East Side goes quiet after ten, and we're not going to pretend otherwise. That's the point of it for a lot of people. If you're traveling with kids, or you're here for work and need to sleep, or you just don't want a bar under your window, quiet is a feature you'd otherwise pay for. If you're 26 and here for four nights of going out, quiet is a bug.
Mornings
The East Side wins mornings. Central Park at seven in the morning, before the park fills up, is the best hour in New York. The Reservoir loop is a mile and a half of soft track with the skyline on three sides, and from East 62nd Street you're at the Fifth Avenue entrance at 60th in about eight minutes. Museum Mile opens at ten and you can be first through the door at the Met without a subway ride.
Williamsburg mornings are coffee and the waterfront, which is lovely, but the walk-in cultural stuff is across the river.
Space and what you get for the money
Both neighborhoods give you more room than Midtown does. Williamsburg's supply skews toward apartment rentals and newer buildings on the waterfront. Ours are apartments too: studios through to the whole house, each with its own front door and a kitchen, which is what makes a longer stay work. No lobby, no key card. If you're coming as a family or a group, the apartment format matters more than the borough.
One thing worth checking before you book anything: New York's short-term rental rules changed in recent years and a lot of under-30-night apartment listings came off the market. Confirm what you're booking is licensed to host you for the nights you want, whichever side of the river you land on.
Who should pick which
Pick Williamsburg if the trip is food and nightlife first, you're happy to transfer for museums, and you want New York at its least touristed.
Pick the Upper East Side if you're here for the park and the museums, you need a fast line into Midtown, you're traveling with kids or parents, or you want to actually sleep. And if you want both, stay on this side and take the F over for one long evening. Coming home against the crowd at midnight is easy.