In traditional pharmaceutics, drug–crystalline nanoparticles and drug–polymer composites are frequently explored for their ability to modify drug release profiles. In this study, a novel sort of hybrid with a coating of acyclovir crystalline nanoparticles on acyclovir-polyacrylonitrile composites was fabricated using modified, coaxial electrospinning processes. The developed acyclovir-polyacrylonitrile at the acyclovir nanohybrids was loaded with various amounts of acyclovir, which could be realized simply by adjusting the sheath fluid flow rates. Compared with the electrospun composite nanofibers from a single-fluid blending process, the nanohybrids showed advantages of modifying the acyclovir release profiles in the following aspects: (1) the initial release amount was more accurately and intentionally controlled; (2) the later sustained release was nearer to a zero-order kinetic process; and (3) the release amounts at different stages could be easily allocated by the sheath fluid flow rate. X-ray diffraction results verified that the acyclovir nanoparticles were in a crystalline state, and Fourier-transform infrared spectra verified that the drug acyclovir and the polymer polyacrylonitrile had a good compatibility. The protocols reported here could pave the way for developing new types of functional nanostructures.