The recommended route from the US is to enter Mexico through Mexicali, and drive straight down Highway 5 into San Felipe. The 120 mile stretch of highway is in good condition, which makes for fairly safe and easy travel. This is the route we always take. This is also the route that my parents used to always take. This road is paved and in decent condition but dont go too fast because there are areas with pot holes and a few sharp turns.
As you head out of Mexicali you will head on out a straight stretch of road. You will pass a few camp grounds, mountains, then sand dunes, then straight desert for miles.
You can also drive to San Felipe from Ensenada, Mexico on Highway 3, but this highway is a lot tougher to drive. If you are towing a boat or trailer, this route is not recommended. It is about 150 miles from Ensenada to San Felipe. I have never taken this route but i have always been warned not too. i have decided to to find out for myself why, i just would rather take the 5.
We crossed the border at Calexico/Mexicali. You can use Highway 5 to go from Mexicali to San Felipe. For the first few miles it's 4 lanes and will then change into 2 lanes, one coming, one going. Driving time is 2 hours.
If you are coming from Ensenada, use Highway 3 to San Felipe.
Though there is are four daily buses from Mexicali to San Felipe, it's much easier to go there by car. I did rent one in Mexicali and drove south about 150 Kms on a well paved road (n.5), through beautiful desert sceneries. There are a couple of military checkpoints, but they are very straightforward. There is no town between Mexicali and San Felipe and about half way you'll cross Laguna Salada, a scenic dry floodplain close to river Colorado.