In this work, a new macroporous molecularly imprinted cryogel (MIP composite cryogel) was synthesized by glutaraldehyde cross-linking reaction of poly(vinyl alcohol) (PVA) particles and amino-modified molecularly imprinted core-shell nanoparticles. The MIP core-shell nanoparticles were prepared using propranolol as a template by one-pot precipitation polymerization with sequential monomer addition. The characteristics of the MIP composite cryogel were studied by scanning electron microscopy (SEM) and texture analyzer. The macroporous structure of the composite (with the pore size varying from a few micrometers to 100 μm) enabled high mass transfer of particulate-containing fluids. In a solid phase extraction (SPE) process, the efficiency and selectivity of the MIP composite cryogel were investigated, where the cryogel was used as an affinity matrix to remove propranolol from aqueous solution as well as from complex plasma sample without prior protein precipitation. The MIP composite cryogel maintained high selectivity and stability and could be used repeatedly after regeneration.