Proteins and enzymes can be encapsulated in nanoporous gels to develop novel technologies for biosensing, biocatalysis, and biosynthesis. When encapsulated, certain macromolecules retain high levels of activity and functionality and are more resistant to denaturation when exposed to extremes of pH and temperature. We have utilized intrinsic fluorescence and Fourier transform infrared spectroscopy to determine the structural transitions of encapsulated lysozyme in the range of -120°C<T<100°C. At cryogenic temperatures encapsulated lysozyme did not show cold denaturation, instead became more structured. However, at high temperatures, the onset of heat denaturation of confined lysozyme was reduced by 15°C when compared with lysozyme in solution. Altered dynamics of the solvent and pore size distribution of the nanopores in the matrix appear to be key factors influencing the decrease in the denaturation temperature.