The mid-infrared spectra of isoprene (2-methyl-1,3-butadiene) dissolved in liquid xenon at temperatures ranging from 164 K to 178 K were obtained using a Fourier transform infrared spectrophotometer and a low temperature cryostat. Additionally, spectra in the C–H region (2800–3200 cm−1) were obtained in liquid argon at 86 K. Spectra in cryogenic liquids show all hidden bands underneath the gas phase spectra. Frequencies of isoprene in liquid argon and liquid xenon solutions are lower with respect to gas phase. Density functional theory (DFT) was employed to calculate vibrational frequencies. Solvent effects were studied using the polarizable continuum model (PCM) demonstrating qualitative agreement with experimental frequency shifts in liquid Ar and Xe. This investigation is important for IR absorption studies of planetary atmospheres where the temperatures are similar (80 K–200 K) and the spectra could resemble the pseudo gas spectra in cryogenic liquids.