The East Lansing, Michigan native spent two seasons with Sault Ste. Marie of the NAJHL before enrolling at Michigan State in 1999-00 where he spent three seasons capturing the prestigious Hobey Baker Memorial Award in 2001 and was a finalist in 2002.

Miller became the NCAA's career shutout leader with 26 and his 950 save percentage in 2000-01 was the best single-season mark in NCAA history. The cousin of Kip, Kevin and Kelly Miller, Ryan backed up NHLers Robert Esche and Rick DiPietro on Team USA at the 2001 World Junior Championships before making his professional debut in 2002-03.

In his first two seasons with the Sabres organization, Miller spent the better part of his playing time with the AHL's Rochester Americans while seeing limited action with the parent club in Buffalo.

In 2005-06, Miller would establish himself as a starting goaltender in the NHL and lead the surprise Buffalo Sabres to the Eastern Conference Finals. Despite Miller's solid playoff performance, the Sabres would finish one game short of advancing to the Stanley Cup Finals. In the Summer of 2006, the Sabres signed the goaltender to a three-year deal. With the Sabres Miller would grow into one of the league's elite goaltenders, consistently posting goals against averages under three.

In 2010, Miller was the cornerstone of the US Olympic team that brought home the silver medal in a thrilling overtime final at the Olympic Winter Games in Vancouver.

Following his strong showing at the Olympic games, Miller returned to Buffalo and provided the Sabres with the same such brilliance. He posted career bests in goals against average (2.22) and save percentage (.929) and set the Sabres record for wins in a season with 41, breaking his own previous mark. For his efforts, he was awarded the Vezina Trophy as the NHL's top goaltender for the 2009-10 season, the first Sabre to receive the honour since Dominik Hasek.