Coloration of mefenamic acid (MFA) was investigated in the presence of mesoporous silica FSM-16 with 16.0 Å (Oc) and 45.0 Å (Doc) pore diameter. The color change of MFA/FSM-16 physical mixture from white to deep blue was observed by sealed-heating (SH) and the subsequent humidification (HU). The coloration and the color difference were caused by the changes of chroma and lightness. In the case of MFA/FSM-16 (Oc), coloration was not observed by SH treatment only. Powder X-ray diffraction data indicated that difference of the dispersed states of MFA molecules in FSM-16 mesopore affected the coloration. MFA adsorbed on the silica surface and MFA in the mesopore were differentiated by thermogravimetric analysis. Solid-state ¹³C-NMR showed that the molecular mobility of MFA was increased in the dispersed state in FSM-16 mesopores compared to the crystalline state. Structural changes of silanol groups in FSM-16 by humidification were observed by solid-state ²⁹Si-NMR. MFA adsorption in FSM-16 mesopore by SH as well as changes of the surface state of FSM-16 by HU affected the coloration of MFA.