O'Keefe will control the Italy v Scotland game in Rome on February 22 and the England v Wales game at Twickenham on March 7.
Williams will referee the Scotland v France Test at Murrayfield on March 8 and will be an assistant referee for France v Ireland at Stade de France in Paris on March 14.
Mike Fraser has been appointed an assistant referee and will be on the sideline at Cardiff for the Wales v Italy game on February 1 and a week later he will be in Dublin in the same role for the Ireland v Wales game.
Brendon Pickerill will be an assistant referee for the France v England game in Paris on February 2 and will be at the same ground a week later in the same role for France v Italy.
Glenn Newman has been appointed a TMO for the Ireland-Scotland game on February 1 and for the Ireland-Wales game a week later.
A feature of the appointments is that Welsh referee Nigel Owens has been appointed to the France v England game, his 98th Test, while England referee Wayne Barnes will control the France v Ireland game - his 90th Test.
World Rugby chairman Sir Bill Beaumont said: "Following an incredible Rugby World Cup in Japan, the rugby family is now anticipating the road to Rugby World Cup 2023 with all eyes on the Six Nations Championship.
"Just like the teams, the preparation for France 2023 begins now for match officials. Our goal is continuous improvement, accuracy and consistency of decision-making and this selection represents the continuation of that journey with a selection that features a strong blend of huge experience and the best young talent."
World Rugby high performance match official manager Alain Rolland said there was plenty of excitement and motivation heading into a new decade in the international game.
"We have a strong team ethic, a superb group of match officials and we are excited about the young talent that is coming through the ranks from the Under-20 championship and elite club environment.
"Our goal is always clear, consistent and accurate decision-making and while there is no change in emphasis, we will continue to build on what we achieved at Rugby World Cup 2019, working with the teams to ensure the best possible experience for players and fans," he said.