Head coach Danny Wilson has made two further changes behind, preferring Dan Fish to Matthew Morgan at full-back and handing Garyn Smith his first start of the season.
And after slipping to a slender defeat to Leinster last week, Wilson is determined to see a response at the Liberty Stadium.
He said: "Following last weekend, our first defeat of the season, we have had a good review and view it as a missed opportunity to beat a good Leinster side.
"There are a couple of areas we have identified that we want to improve upon going into the Ospreys game.
"They are a good team with a lot of high profile players and are well coached. It is going to be a tough game but it is a Welsh derby and everyone is excited and motivated for the first one of the season.
"We go into the game on the back of a good start, with four wins from five, so we have a bit of confidence but we know it will be a big test at the Liberty Stadium."
With Navidi and Cook stepping up from the bench, both James Down and Cam Dolan return to the match-day 23 for the first time since the opening game of season.
Cardiff Blues won four out of six Welsh derbies last season and are targeting their first Ospreys scalp since 2010.
Cardiff Blues: Dan Fish; Blaine Scully, Garyn Smith, Rey Lee-Lo, Tom James; Gareth Anscombe, Lloyd Williams; Gethin Jenkins (capt), Kristian Dacey, Taufa'ao Filise, Macauley Cook, Josh Turnbull, Josh Navidi, Ellis Jenkins, Nick Williams
Replacements: Matthew Rees, Rhys Gill, Scott Andrews, James Down, Cam Dolan, Tomos Williams, Steven Shingler, Matthew Morgan
