Autosomal recessive primary microcephaly is a neurodevelopmental disorder associated with reduced brain size and intellectual disability. ASPM (abnormal spindle-like microcephaly-associated) is the most common recessive microcephaly gene, but the underlying mechanism is poorly understood. Here, we show that calmodulin function as a vital regulator of ASPM by interacting with its IQ-region. The complex of ASPM IQ-region and apo_calmodulin was purified and biochemically characterized with a 1:8 stoichiometry by size exclusion chromatography coupled with multi-angle static light scattering (SEC-MALS) and circular dichroism spectroscopy (CD). Interestingly, the binding ratio of ASPM IQ-region with Ca2+_calmodulin changed to 1:7 in the presence of Ca2+. In addition, by comparing the CD spectra with and without Ca2+, the ASPM-Calmodulin complex showed Ca2+-dependent thermal stability change. Taken together these results suggested a Ca2+-induced regulation mechanism of ASPM-calmodulin interaction.