Peroxydisulfate (PDS) activation has attracted much attention for the treatment of drinking water systems. In this work, Ni-doped MgAl layered double hydroxides (Ni-LDHs, Ni:Mg = 1:100 to 1:1, molar ratio) were prepared for the activation of PDS via intercalation. Compared with the case without Ni, doping with Ni resulted in much higher phenol degradation at the same PDS dosage. This was attributed to the activation of PDS, as the PDS consumption increased with increasing Ni doping amount. Moreover, radicals corresponding to organic decomposition were detected in the presence of Ni. Physical characterization results reveal that Ni(II) was converted to Ni(III) with PDS and then reduced back to Ni(II) during organic decomposition. To our best knowledge, this is the first study to report a cycle of Ni(II)-Ni(III)-Ni(II) in LDHs for the efficient activation of PDS. This effect was also observed in cases of odorous substances such as 4-bromophenol, 2-methylisoborneol, and geosmin. Our work provides a promising approach for the activation of PDS by Ni-LDHs.