Granada has no shortage of tour operators, many of whom have international connections. As a result, it's easy to find all-inclusive packages to the area, which should include at least a day of exploring the city before moving on to see either La Isletas, Laguna de Apoyo or, if you've got a bit more time, the Isla de Ometepe.
From Granada, it's easy to book tours to the surrounding region. Volcano trips, particularly to Mombacho or Masaya, are also quite popular, though most of Nicaragua's volcanoes are within day-trip distance.
If you're in Granada and heading abroad CAST (see listing) has connections in Costa Rica and Panama for booking international tours. A few other agencies have offices in Costa Rica.
Michael Karanicolas is awesome.