This paper reports a nanomagnetic polyhedral oligomeric silsesquioxanes (POSS)-directing strategy toward construction of molecularly imprinted hybrid materials for antibiotic residues determination in milk samples. The imprinted polymeric layer was facilely obtained through the copolymerization of active vinyl groups present on the nanomagnetic POSS (Fe3O4@POSS) surface and functional monomer (methacrylic acid) binding with template (enrofloxacin). Herein, the octavinyl POSS acted as not only the building blocks for hybrid rigid architectures but also the cross-linker for the formation of effective recognition sites during the imprinting process. The molecularly imprinted Fe3O4@POSS nanoparticles (Fe3O4@MI-POSS) demonstrated much higher adsorption capacity and selectivity toward enrofloxacin molecules and its analogs than the non-imprinted Fe3O4@POSS (Fe3O4@NI-POSS) materials. The imprinted particles were applied as a selective sorbent in solid-phase extraction focusing upon sample pretreatment in complex matrices prior to chromatographic analysis. The three FQs (ofloxacin, enrofloxacin, danofloxacin) could be selectively extracted from the biological matrix, while the matrix interferences were effectively eliminated simultaneously under the optimum extraction conditions. A simple, rapid and sensitive method based on the Fe3O4@MI-POSS material combined with HPLC-UV detection was then established for the simultaneous determination of three FQs from milk samples. The average recoveries of the three FQs were in the range of 75.6-108.9%. The relative standard deviations of intra- and inter-day ranging from 2.91 to 8.87% and from 3.6 to 11.5%, respectively. The limits of detections (S/N=3) were between 1.76 and 12.42 ng mL(-1). It demonstrates the effectiveness of trace analysis in complicated biological matrices utilizing magnetic separation in combination with molecularly imprinted solid-phase extraction, the rich chemistry of POSS makes it possible to be an ideal platform for generating molecular imprinted hybrid materials is also exhibited.