This study was conducted to investigate the effect of laser beam irradiation from a novel non-confocal laser Raman microscope on the stability of a photo-sensitive drug. The non-confocal Raman microscopy, which irradiates a low-power unfocused laser beam on the surface of the samples by controlling of optical system, was applied to characterize the stability of nifedipine as a photo-sensitive drug model. The time-dependent changes in the Raman spectra of nifedipine were monitored in order to evaluate the degradation of nifedipine during laser irradiation. The results were compared with the Raman spectra measured by using the confocal laser Raman microscopy which irradiates a low-power focused laser beam. The intensity of some peaks in the confocal Raman spectra significantly decreased depending on the irradiation-time length, compared to the non-confocal Raman macroscopic analysis. The photodegradation of nifedipine caused by the laser irradiation followed the first-order kinetics. The degradation rate constants of nifedipine with the non-confocal analysis were lower than those of nifedipine with the confocal analysis. Thus, the novel non-confocal laser Raman microscopy can be applied to reduce the degradation of the photo-sensitive drug during laser irradiation, and the results suggest that the non-confocal laser Raman microscopy will be a useful technique for the measuring of Raman spectra of photo-sensitive materials with a long-term exposure.