Gain amplification and coherent lasing lines through random lasing (RL) can be produced by a random distribution of scatterers in a gain medium. If these amplified light sources can be seamlessly integrated into biological systems, they can have useful bio-optical applications, such as highly accurate sensing and high-resolution imaging. In this paper, a fully biocompatible light source showing RL and amplified spontaneous emission (ASE) with a reduced threshold is reported. Random cavities were induced in a biocompatible silk protein film by incorporating an inverse opal with an inherent disorder and a biocompatible dye for optical gain into the film. By choosing the appropriate air-sphere diameters, clear RL spikes in the emission spectra that were clearly distinguished from those of the ASE were observed in the silk inverse opal (SIO) with optical gain. Additionally, the RL output exhibited spatial coherence; however, the ASE did not. The high surface-to-volume ratio and amplification of the SIO led to highly efficient chemosensing in the detection of hydrogen chloride vapor. Moreover, SIO could be miniaturized to be made suitable for injection into biological tissues and obtain RL signals. Our results, which open the way for the development of a new generation of miniaturized bio-lasers, may be considered as the first example of engineered RL with biocompatible materials.