Coral-like porous Mg–Al layered double hydroxide (LDH) microspheres have been synthesized for the first time in a nonaqueous polar solvent/surfactant system of EG (ethylene glycol)/methanol/DS (dodecyl sulfate) via a one-pot method. The mechanism of forming the unique LDH structure was investigated. It has been found that the solvation effects of the organic polar solvents are crucial for the retarded nucleation and crystallization rates. The presence of surfactant DS further prohibits the growth of the LDH nanoparticles to larger hexagonal platelets. A detailed study on the effects of solvothermal reaction temperature, duration and solvent type has revealed the formation of an intermediate compact microsphere structure via self-assembly of LDH nanoparticles. The compact microspheres further evolve to form the coral-like porous structure with constituent sub-nanoplatelets through recrystallization. The resultant LDH microspheres are intercalated with DS anions, which can be easily exchanged with other anions with functional properties, such as drugs. In this study, the DS anions in the pristine compact or coral-like Mg–Al LDH microspheres were exchanged with a few drug compounds, such as ibuprofen, naproxen and 4-biphenylacetic acid in their anionic forms. The drug-intercalated LDHs retain the morphological features of the pristine microspheres. It is expected that well defined LDH microspheres formed at a large scale by the method developed in this work may exhibit great advantages in practical applications compared with the random aggregates of conventional hexagonal platelets.