It takes about 5 hours driving from Havana to Cayo Santa Maria along the Motorway and a little bit longer if you take the north road and drive through small towns. Which I recommend if you do not mind driving for this long.
A domestic flight takes 45 minutes but you will have to be ready about two ours earlier at the lobby of your hotel in Havana.
The cost of a taxi from Havana to Cayo Santa Maria is around 300.00 CUC and the domestic flight cost is around 100.00 CUC return.