Technologies for flexible I/O protocol acceleration include a computing device having a root complex, a smart endpoint coupled to the root complex, and an offload complex coupled to the smart endpoint. The smart endpoint receives an I/O transaction that originates from the root complex and parses the I/O transaction based on an I/O protocol and identifies an I/O command. The smart endpoint may parse the I/O transaction based on endpoint firmware that may be programmed by the computing device. The smart endpoint accelerates the I/O command and provides a smart context to the offload complex. The smart endpoint may copy the I/O command to memory of the smart endpoint or the offload complex. The smart endpoint may identify protocol data based on the I/O command and copy the protocol data to the memory of the smart endpoint or the offload complex. Other embodiments are described and claimed.