My husband and I are planning a weekend trip into manhattan for our anniversary. We will arrive on a saturday early afternoon and have 5:30 dinner reservations at the 21 Club and tickets to the Wedding Singer and staying at the W Hotel in Times Square. We would like to do something on Saturday and Sunday afternoon. Any suggestions? Is the Museum of Modern Art a must see even if you don't truly enjoy museums? Any history museums? What to do in Central Park for the day?

The MOMA is great. I'd also suggest you go up the Empire State Building and maybe walk around Rockefellor Center area (near MOMA)

For a history museum go to Ellis Island. Skip the Statue of Liberty, which will be to crowded and take to long to get to the top. For any activity on a September weekend, get tickets on-line ahead of time.
Put time aside just to wander, stroll Central Park during the day and the Village at night, walk through Grand Central Station.

I'm not sure what you mean exactly by history museums, but the Museum of New York City on the upper east side is one of my favorite museums -- mainly a lot of exhibits about the history of New York and its various aspects.

I think the setting of the Cloisters rivals much of Central Park (although only a tiny fraction the size) and on weekends is not nearly so crowded. It's wonderful on a nice day.

Backstage tours of the Metropolitan Opera, Carnegie Hall, or Radio City Music Hall are all fun and different if you like that sort of thing.

I think I'd chose going to the Top of the Rock (Rockefeller Center) over Empire State Building -- less hassle and even better views.

If you're not into museums, I wouldn't do MOMA (IMO) I think the Metropolitan museum is more interesting for a non museum person since the building itself is awesome and there are so many things to see besides paintings. But there's nothing that says you have to do any museums. Sat. you could walk to Rockefeller Center, have a look around there and do Top of the Rock. Then have a walk up Fifth Ave. to the park if it's a nice day. For what to do/see
centralparknyc.org

Om Sunday you might want to consider a walking tour. bigonion.com has several that are historical tours. There's a free walking tour of the lower east side at 11 am that meets at Katz's deli. Here's a link to a bunch of free walking tours including that one.
http://nymag.com/guides/cheap/walkingtours/

Another popular tour is one of the eating tours given by foodsofny.com

The NY Historical Society is near the Museum of Natural History. The museum Neo mentions is the Mus of the City of NY.

Another very popular stop for interesting history is the Tenement Museum. Must book ahead. See the way life was for immigrants on the lower east side.
http://www.tenement.org/