Assuming you are renting a car at the airport, make sure you have a clear understanding of how to get to the Autopista from the car rental area (not too hard). Once you are on the road, you go straight. You can't miss Ponce-quite obvious. Going over the mountains is quite spectacular.

You will find the road exactly like most freeways in the mainland U.S.

Highway Route 52 will take you directly from San Juan to Ponce nonstop. It is a divided toll highway through the interior mountains to the southern coastal city of Ponce. It is similar to an interstate highway in the States. Bring along a roll of quarters for the tolls along the way. Also, if you plan to travel a lot through the island, stop at a gasoline station and get yourself a detailed Puerto Rico map. Most Esso stations carry them. It will cost you 4 or 5 dollars, but it is indispensible. The map you'll get from the car rental agency is virtually worthless. Also distances in Puerto Rico are measured in kilometers and gasoline is sold by the liter. Speed limit signs are in miles per hour.

Very, very easy, as they said. In any case, it should not take you more than 2 hours (probably about 1:40-1:45) at night with no rush traffic. It is mostly a toll road and quite safe, nevertheless, you go trough the center mountain range and it has some steep and curvy areas you are not familiar with, and we puertorricans drive a bit differently, so use your best precautions and get exact directions to exit and enter San Juan and Ponce. They are both large cities, especially San Juan, with many exits and highways. At the toll road, just follow the signs.

Ask the hotel you are staying which exit number you should use to get there. You wont miss the huge "PONCE" red letters on the road when you are about to get there! Driving at 65mph you should get there in 1:20 - 1:40 hrs. The night view of the lights in the Cayey -Beatriz area is spectacular.

just to add my two cents because I think you have enough good advice already. I repeat the only tricky bit is actually getting from the hotel and onto 22, which will merge right into 52, which takes you to Ponce.

Insider's tip, in 52 you will find sections with three lanes, take the middle lane, the right lane is commonly in bad shape due to heavy trucks. In those sections with only two lanes, if you find the condition of the right lane too bad, feel free to do as the locals do and take the left lane. Police do not really enforce that the left lane be used only for passing.