Mucins are vital components contributing to the unique lubrication properties of human whole saliva. For patients receiving medication and or treatment such as diabetes or radiotherapy, xerostomia (dry mouth) is a common with numerous and deleterious side effects. Although products exist on the market to relive the symptoms of Xerostomia there remains a drive to formulate a biocompatible lubricant that replicate the functionality offered by the natural biological environment. Herein, a combination of mucin and thiolated polyethylene glycol (PEG-SH) was proposed as a new saliva substitute. Mucin and PEG-SH molecules could form hydrated layers immediately by chemisorption. Meanwhile, the chemical interactions between mucin and PEG-SH molecules also promoted the formation of a mixed layer. All the pre-formed layers could decrease friction and had the potential to decrease wear, especially mucin and PEG-SH mixed layer when compared to mucin only solutions. Further investigations of tribological mechanism implied that the excellent lubrication performance of mixed layer with long effectiveness was contributed to the friction-reducing effect of PEG/mucin molecules and the mucoadhesive property of mucin. The study provides a guide for using mucin as a mucoadhesive agent to stable lubricative polymers with low molecular weight as novel salivary substitutes for lubrication.