Abstract Cosmic rays (CRs) govern the energetics of present-day galaxies and might have also played a pivotal role during the Epoch of Reionization. In particular, energy deposition by low-energy (E ≲ 10 MeV) CRs, accelerated by the first supernovae, might have heated and ionized the neutral intergalactic medium (IGM) well before (z ≈ 20) it was reionized, significantly adding to the similar effect by X-rays or dark matter annihilations. Using a simple, but physically motivated reionization model, and a thorough implementation of CR energy losses, we show that CRs contribute negligibly to IGM ionization, but heat it substantially, raising its temperature by ΔT = 10–200 K by z = 10, depending on the CR injection spectrum. Whether this IGM pre-heating is uniform or clustered around the first galaxies depends on CR diffusion, which, in turn, is governed by the efficiency of self-confinement due to plasma streaming instabilities that we discuss in detail. This aspect is crucial to interpret future H i 21-cm observations, which can be used to gain unique information on the strength and structure of early intergalactic magnetic fields, and the efficiency of CR acceleration by the first supernovae.