Foundation design of high-rise buildings in karst region is always the difficult point of ground treatment in a construction project. The karst foundation has the properties that many soil caves and caverns are found; rock surface is greatly undulating; ground water there is unpredictable and so on. These complex conditions in karst area to some extent make the foundation design of high-rise buildings extremely challenged. In this paper, a foundation design of high-rise buildings on cobbly soil karst ground is introduced in which the abundant and reliable data were obtained through the loading test of undisturbed soil, ramming-reamed pile composite foundation, punching pile composite foundation and other in-situ tests. According to the scientific analysis of test results, thickness of covering layer and development of karst, the scheme of ground treatment with multiple types of pile below raft foundation is adopted at last. This scheme can not only satisfy the requests of the load and the settlement, but also consider the risks of the cave collapse and the differential settlement, which is even more economical. And the calculated settlement was made to be compared with actual observations to illustrate the rationality of the chosen scheme. It will be a good reference for handling ground treatment of high-rise buildings in complex karst region.