I'm looking for hotel recommendations for 4 nights in Crete. Should we plan to stay in one place, or 2 locations to see the most of the island?

You can't see most of the island in 4 days, you'll need at least 2 weeks and a rental car. With only 4 nights pick one spot and explore as best you can with a car in that region of the island. I recommend Chania in the northwest quadrant.

IF you are flying in and out, you can come in/out of either Chania or Heraklion. If you use fast-ferries for either arrival or departure, they are only from or to Santorini (regular o'nite ferries are to either port).

Of course you can rent car on arrival & drive to other on leaving...but that uses 1/2 a day.

Best to Decide on in/ou transport FIRST, and then look for hotels...the other way around can lead to trouble.

Just to second Brotherlee we spent two weeks in Crete last summer and only toured the western part of the Island.
We were unable to finish our planned itinerary because when we found a location we liked we stayed longer and just blew our schedule.
Chania alone will take 4 days.

Frankly unless there is some overwhelming reason forcing you to go to Crete I would suggest 4 days really is not worth it.

Thanks to all for the advice. Are there other places, rather than Crete, to spend the remaining 4 days we will have in Greece (after Athens and Santorini)?

A good combination with Santorini is Naxos or Paros. They are quite different from Santorini with fewer tourists.
After visiting both Naxos and Paros on several occasions our favorite is Naxos. It has a nice balance of things to enjoy including the Venetian era buildings in the Kastro area of town with its twisting narrow streets. St George beach is on the edge of town within easy walking distance. Better beaches are a half hour bus ride out on the West Coast (1.4 euro.) Rent a car and visit the wonderful mountain villages. On the way there are several interesting antiquities dating back to the 6th century.
In Naxos you will very likely have an opportunity to meet local Greeks who live there all year round.
4 days will give you about enough time to really explore.
The nice thing about going to Naxos from Santorini is you are traveling in a straight line back toward Athens on a direct ferry route.
Generally it is best to keep one day at the end of the trip for the last night in Athens just in case there is some sort of a hiccup with your return ferry.