Removal of two typical antibiotics (norfloxacin and tylosin) at trace level in turbid water simultaneously containing natural organic matters (NOMs) was conducted using two phenylalanine (Phe)-modified-chitosan flocculants (CHS-Phe and CHS-PPhe) with different molecular architectures. Response surface methodology (RSM) was applied for interactive effects evaluation and optimization of various parameters. CHS-Phe with linear molecular architecture displays higher removal efficiencies of antibiotics than commercial flocculants. By contrast, CHS-PPhe, owning the same Phe functional groups but comb-like architecture (polyPhe polymer branches grafted on chitosan backbone), shows poor performance. Deep mechanism investigations indicated that, for hydrophilic and flexible CHS-Phe linear molecules, bridging and sweeping flocculation for antibiotics were enhanced by electrostatic attraction, pi-electron-containing interaction, and H-bond between introduced Phe groups and antibiotic molecules. However, for comb-like CHS-PPhe, excessively hydrophobic polyPhe branches aggregated to coils. This phenomenon caused fewer exposed flocculation sites outwards, although the interactions of Phe-antibiotic still existed. 3D response surfaces of CHS-Phe generated by RSM exhibited that, concentrations of coexisting kaolin and HA, as well as pH and flocculant dosage, can be controlled to obtain desired performance. This work enriches the knowledge of effect of molecular architecture of flocculants on contaminant removal, and provides guidance for flocculation parameter control.