Fucoidan was chosen a substitute for alginate in chitosan-based polyelectrolytes or polyiones because it is negatively charged and possesses pharmacological properties. The fucoidan-chitosan nanospheres were prepared by the sonification method, and different formulation variables were investigated to get regular and round microspheres. Single factor and orthogonal experiments were carried out in this process, and nanospheres were finally prepared successfully. Stability tests revealed that some of the spheres were stable over one week. Combined with the drug loading/release profiles when using bovine serum albumin and capecitabine as model drugs for peptide and small molecule drug respectively, it can be concluded that the nanospheres may have potential applications in drug delivery.