In this study, the rejection of six differently charged antibiotics by nanofiber composite forward osmosis (NCFO) membranes was investigated. Membrane performance and antibiotic-rejection mechanisms were revealed through varying operating conditions. Models were established to forecast the rejection of the antibiotics. Results showed that water flux of the NCFO membrane achieved as high as 49 LMH, and rejection of the six antibiotics were higher than 98% using 1 M NaCl as draw solution. The antibiotic rejection was mainly dominated by steric hindrance and electrostatic interaction. Neutral and macromolecular-charged antibiotics were barely affected by the steric hindrance. Moreover, small molecular-charged antibiotics were greatly affected by the electrostatic interaction. The draw solution caused an increase in ionic strength, and the negative charge on the surface of the membrane was affected by electrostatic shielding. Furthermore, a model including two algorithms was established to obtain the permeability coefficients and the structural parameters to simulate the FO process. The results demonstrated that this model could successfully simulate the whole process.