The most common complaint in people with single-sided deafness (SSD) is difficulty in understanding speech in a noisy environment. Moreover, the neural mechanism of speech-in-noise (SiN) perception in SSD individuals is still poorly understood. In this study, we measured the cortical activity in SSD participants during a SiN task to compare with a speech-in-quiet (SiQ) task. Dipole source analysis revealed left hemispheric dominance in both left- and right-sided SSD group. Contrary to SiN listening, this hemispheric difference was not found during SiQ listening in either group. In addition, cortical activation in the right-sided SSD individuals was independent of the location of sound whereas activation sites in the left-sided SSD group were altered by the sound location. Examining the neural-behavioral relationship revealed that N1 activation is associated with the duration of deafness and the SiN perception ability of individuals with SSD. Our findings indicate that SiN listening is processed differently in the brains of left and right SSD individuals.