The invention discloses a true random number generation method based on a CPU clock and a USB independent clock, the method comprises the following steps: taking a jitter difference of the CPU clock and the USB independent clock as a random noise source, generating a random number seed, performing hash operation to the random number seed through a hash algorithm, and generating a needed true random number. The method provided by the invention only depends on a CPU main clock and a USB module independent clock which are generally arranged on modern CPU circuit boards in the aspect of hardware,compared with a method of generating the true random number through operations, such as externally connecting a physical noise source, externally connecting various clock source counting circuits, accessing to peripherals by a CPU or repeating memory access operation, the method provided by the invention is more simpler, convenient and efficient, and can be used for occasions where the true randomnumber is needed in information security processing operations, such as secret key generation, digital signature and secret key negotiation.