Worcester forward Horsman faces ankle surgery later this week, and he is likely to be sidelined for around five months.
Horsman, 27, made his Wales debut off the replacements' bench against New Zealand in November, and then started Tests against Fiji, South Africa and Australia.
The powerful scrummager was an integral part of Ruddock's Six Nations plans, but he now becomes the latest Welsh injury casualty.
Back-row forward Ryan Jones, lock Brent Cockbain and full-back Kevin Morgan, who all played key roles in last season's Six Nations Grand Slam triumph, have already been ruled out of the tournament, while centre Tom Shanklin is also likely to miss all five games.
Gavin Henson is currently banned for the opening three matches, although he will appeal against a 10-week suspension in Dublin on Tuesday for elbowing Leicester prop Alex Moreno during a European Cup clash between the Ospreys and Leicester last month.
Wales kick off their Six Nations campaign against world champions England at Twickenham on February 4.
Worcester have confirmed Horsman will undergo surgery on Thursday, having suffered with an ankle problem since October.
"Chris has been playing through the pain from his ankle for some time now, and the point has been reached where surgery is the only real option," said Warriors rugby director John Brain.
"It is a blow for us, but not an unexpected one - and we have enough quality props at the club to deal with the situation.
"Until the surgery has been completed, we can't be sure exactly how long he will be out of the game.
"But we will do everything we can at the club to ensure that his recovery will be complete."
Former Bath prop Horsman qualified to play for Wales earlier this season, having completed a three-year residency period.