Drafted in the 14th round of the 1960 NFL Draft from Dayton, Bob DeMarco arrived in St. Louis with modest expectations but soon became a key part of the team. After playing a few games as a rookie guard in 1961, he took over as the starting center in 1962 and kept that role for the rest of the decade.

DeMarco was a resilient and technically skilled interior blocker, thriving in an era focused on physical, ground-and-pound football. Renowned for his sharp pre-snap line calls and quick snap-and-step execution, he consistently managed tough head-up nose tackles while creating running lanes for backs like John David Crow and Johnny Roland. His durability at the pivot offered essential continuity for an offense that frequently changed backfield setups during the 1960s.

DeMarco earned his first national recognition during the 1963 campaign, garnering his first Pro Bowl selection and AP Second-Team All-Pro honors. He maintained a high standard of play at center, securing a second Pro Bowl invitation in 1965.

His career peaked in the 1967 season, when his dominant play in the trenches earned him consensus First-Team All-Pro honors and his third Pro Bowl selection. He continued to build on his reputation with a Second-Team All-Pro selection in 1968, cementing his status as one of the NFC's top interior linemen. From 1962 to 1969, DeMarco started 103 of 107 games at center for St. Louis, anchoring the offensive line during the height of his career.

Following nine seasons in St. Louis, DeMarco departed after the 1969 campaign. He went on to play six more seasons across stints with Miami, Cleveland, and Los Angeles before retiring in 1975 with 185 total games played.