The ancient Silk Road's most important commodity was not silk but the knowledge that traveled alongside it. Languages, religious texts, artistic traditions, mathematical knowledge, agricultural plants, and disease pathogens all moved along the same routes that carried luxury goods.

The spread of plague along Silk Road routes is one of the most consequential unintended consequences in ancient history. The Antonine Plague (165-180 AD) may have entered the Roman world through returning soldiers from the Parthian campaign; its ultimate origin is uncertain. The Justinianic Plague (541-549 AD) is the first clearly documented pandemic of Yersinia pestis (bubonic plague), and it moved from Central Asia to the Eastern Mediterranean along trade routes.

The spread of cultivated plants is more positive in its consequences. Cotton reached the Mediterranean world from India via trade. Sugar cane spread from South Asia westward. New crop varieties moved constantly along trade routes, incrementally improving agricultural yields in different regions.

The most important single knowledge transfer along the Silk Road may have been papermaking, which traveled from China to the Islamic world in the 8th century and from there to medieval Europe. Paper's replacement of parchment for everyday writing transformed the economics of literacy and ultimately made possible the print revolution of the 15th century.