Two strategies for encapsulating caffeine in ZIF-8 were carried out in this work: (1) one-step, in situ encapsulation where caffeine is added to a ZIF-8 synthesis solution and the MOF structure is formed around the entrapped molecule; and (2) ex situ encapsulation whereby caffeine is put into contact with previously synthesized or purchased ZIF-8. The products obtained were analyzed with XRD, TGA, Vis-UV, GC-MS, FTIR, (13)C NMR, and N 1s XPS to compare both encapsulation methods. Chemical and structural evidence indicated that the preferential adsorption site of caffeine molecules inside the ZIF-8 structure is near the methyl and CH groups of 2-methylimidazole ligand. These two groups interact with caffeine by van der Waals forces with methyl groups and via CH···O hydrogen bonds with C═O groups, respectively. In addition, the one-step encapsulation of caffeine in ZIF-8 produced high guest loading (ca. 28 wt % in only 2 h at 25 °C) and controlled release (during 27 days).