Undrafted out of North Texas in 1999, the Waxahachie native entered the league with the Dallas Cowboys, trying to convert from college tight end to fullback. After being cut, Brian Waters landed in Kansas City in 2000, where Dick Vermeil and offensive line coach Willie Roaf/Will Shields quickly saw his true potential on the interior offensive line and shifted the 320-pound powerhouse to left guard.

Waters spent two seasons honing his footwork before seizing the full-time starting left guard job in 2002. Slotting in alongside Willie Roaf and Casey Wiegmann, he quickly evolved into one of the most dominant interior run-blockers in professional football, paving massive lanes for Priest Holmes and Larry Johnson during Kansas City's record-setting offensive explosion in the early 2000s.

His national breakthrough arrived during a historic 2004 campaign. After a 56–10 demolition of Atlanta in which Kansas City poured in an NFL-record eight rushing touchdowns, Waters earned AFC Offensive Player of the Week—becoming the first offensive lineman in NFL history to receive the weekly award. He capped off that stellar year with consensus AP First-Team All-Pro honors and his first Pro Bowl selection.

Waters replicated his First-Team All-Pro form in 2005 while cementing his status as an indispensable locker-room anchor. Over his 11-year run in Missouri, he earned five Pro Bowl nods in a Chiefs uniform (2004, 2005, 2006, 2008, and 2010), and two Second-Team All-Pro nods (2007, 2008), forming one of the most fearsome guard duos in league history alongside Hall of Famer Will Shields.

Beyond his dominance in the trenches, Waters distinguished himself as a generational community leader off the field. Through his 54-82 Foundation—which delivered resources, clothing, and athletic opportunities to underrepresented youth across Texas and Kansas City—he was awarded the prestigious 2009 Walter Payton NFL Man of the Year honor.

After leaving Kansas City in 2010, Waters earned his sixth Pro Bowl selection with New England in 2011 and finished his career with Dallas in 2013. He entered the Chiefs Hall of Fame in 2019.