PurposeTo introduce a new method for generalized RF pulse design using physics‐guided self‐supervised learning (GPS), which uses the Bloch equations as the guiding physics model.Theory and MethodsThe GPS framework consists of a neural network module and a physics module, where the physics module is a Bloch simulator for MRI applications. For RF pulse design, the neural network module maps an input target profile to an RF pulse, which is subsequently loaded into the physics module. Through the supervision of the physics module, the neural network module designs an RF pulse corresponding to the target profile. GPS was applied to design 1D selective, ‐insensitive, saturation, and multidimensional RF pulses, each conventionally requiring dedicated design algorithms. We further demonstrate our method's flexibility and versatility by compensating for experimental and scanner imperfections through online adaptation.ResultsBoth simulations and experiments show that GPS can design a variety of RF pulses with corresponding profiles that agree well with the target input. Despite these verifications, GPS‐designed pulses have unique differences compared to conventional designs, such as achieving ‐insensitivity using different mechanisms and using non‐sampled regions of the conventional design to lower its peak power. Experiments, both ex vivo and in vivo, further verify that it can also be used for online adaptation to correct system imperfections, such as / inhomogeneity.ConclusionThis work demonstrates the generalizability, versatility, and flexibility of the GPS method for designing RF pulses and showcases its utility in several applications.