This is a very frequently asked question, and has no definite answer. Because it depends on the type of traveler you are. Different people like different cities, and different pepople prefer different traveling styles/techniques.
Are you coming to relax? if so, pick one place....maybe 2 and enjoy your short stay. If you want to see a bunch of things and dont mind an exhausting vacation, go a different place every day and see lots of things.
Each city has something different to offer. Granada is where most of the tourists go. And many love it. Others hate it because of that very reason. San Juan Del Sur is the next popular place, and its absolutely gorgeous, but has a reputation of being a young party/drunk town. Which for many, ruins it. Managua has the most options and has the shopping or modern amenities, but many people hate it for all the things that come along with a big city (crime, littering, traffic, etc).
You can have a beach vacation...you can have a small native village vacation, you can have a big city adventure. You could have a carribean island vacation. You could beat the heat and hang out up in the mountains adventure.
My suggestion is to do your research and figure out what kind of vacation you want first, and then come ask specific questions about things if you need more info.