Chrome tanning is the most widely used method in the leather industry; however, the resulting chromium residue causes great harm to both the environment and humans. Inspired by mussel adhesive proteins, a series of Cr 3+ -free, multifunctional, environment-friendly, and amphiphilic poly[L-ε-N-oleoyl lysine-b-(L-threonine-ran-L-DOPA)]s (POLTD) were synthesized and employed as leather tanning agents with fatliquoring and filling effects. These well-degradable polypeptides could determine the hydrothermal stability and mechanical properties of the leathers by different monomer ratios and average molecular weights. Through the orthogonal optimizations of polymer structures and tanning process parameters, results show that POLTD effectively increases the shrinkage temperature of leathers to about 40 °C higher than that of hides, up to 73.5 °C, and thickens the leathers by about 30%. While combined with tanning, POLTD synergies well with Cr 3+ and Al 3+ tanning agents; it not only enhances the absorption and reduces the usage amount of metal tanning agents as well as water pollution, but also improves leather performances, such as the poor washability of Al 3+treated leathers. Coincidentally, POLTD further fills and liquefies the leather collagen fibers in retanning processes and improves the properties of chrome tanning leathers. These findings provide a simple, nonpollution, and environmentally friendly application of polypeptide materials to meet the related technologies toward eco-friendly leather manufacture.