Learn Spanish (Latin America): Ellos manejan por la carretera nueva.

In Spanish, por is used to show movement along, through, or by a place. Because they are actively traveling along the highway, you use por. Using en would sound more like they are just located or parked on the highway, rather than moving along it.

I learned that 'to drive' is conducir. Can I use that instead of manejan?

You can, but in Latin America, manejar is the most common word for driving a vehicle. Conducir is used more in Spain, though people in Latin America will still perfectly understand you if you use it!

Why does nueva come after carretera?

In Spanish, descriptive adjectives like nueva (new) almost always go after the noun they describe. So, 'the new highway' becomes la carretera nueva (literally 'the highway new').

What is the difference between a carretera and a calle?

A carretera is a highway or a major road that usually connects different cities or towns. A calle is a regular street inside a city or neighborhood.