It's an amazing part of the world.
I prefer to overnight in Santiago (stay at Hotel Le Reve, and eat over the road at Il Jardin de Epicureo) and then head up. Try and get a window seat on the right as this side gets the views of the mountains as you fly, including the amazing Aconcagua.
I usually stay at the Terrado in Antofagasta. It's modern, got good service and beautiful sea views from all the rooms. As mentioned previously, Antofagasta isn't much to write home about and I wouldn't go there other than for work.
The rest of the region by contrast is fascinating. Drive from Antofagasta to Calama and onwards to San Pedro de Atacama. I haven't met anyone who hasn't fallen in love with this place. There are trips to the salar (salt desert) where the pink flamingo's wade in the bubbling springs. The Vale de Luna is a short drive/bike away and a must do at sunset. It's an area of strange folded salt hills, natural amphitheatres etc and is quite unique and beautiful. You can ride, bike and take trips up into the volcanoes to see geysers. The town itself is primarily adobe and dirt streets. But don't be fooled. Behind the adobe walls there are great places to stay and excellent restaurants. Picture a restaurant without a roof (why would you need one, it never rains) with a huge fire at the centre and tables all around. Excellent 17th century buildings and and a good museum of pre-Columbian artefacts to see as well
San Pedro is also a good base for day trips to ancient inca ruins, and natural phenomena like the Chui Chui lake (the local town also has a fascinating old church that was constructed from cactus as wood was so scarce).
On the road to Calama its worth taking an hour to visit one of the ghost towns left over from the 19th century nitrate industry. Some are quite well preserved and you marvel at the harshness of the world these people populated.
I hope you enjoy the trip. The desert up there is unique, the Andes awe inspiring and the people wonderful (although it helps to know some Spanish).