The 21-time Grand Slam champion has limited her schedule to just three tournaments so far this season despite missing out in the final of both the Australian Open and Indian Wells before crashing out at the fourth round of the Miami Open last month.
Williams has instead been boosting her profile off the court as she starred alongside Beyonce in the pop superstar's visual album this week.
However, the two-time winner in Madrid faces stiff competition from a wide-open field on her return to action despite the absence of 2014 champion Maria Sharapova after she admitted to failing a drugs test at the Australian Open.
And the German is looking to build on her positive start to the European clay-court season in Madrid and Rome before the French Open next month.
"I know I can play well on clay," said Kerber. "This is the attitude I'll take to Paris."
The faster conditions than a normal clay surface in Madrid due to the slight altitude of the Spanish capital could help Kerber even more.
Two-time champion Petra Kvitova returns to defend her crown at the Caja Magica and strongly believes the conditions favour her style.
"The balls really fly and I think that the players who are just pushing the ball don't really have a chance to finish the ball."
World number five Victoria Azarenka is the most in-form player on the Tour as the Belarusian arrives in Madrid on the back of a 14-match winning streak having won in Indian Wells and Miami, as well as helping her country relegate Russia in the World Group II in the Fed Cup earlier this month.
Home hopes are carried by Garbine Muguruza as the world number four hopes to become the first Spanish woman to win the Madrid Open. However, Muguruza has had a disappointing season so far as she has failed to make it beyond the quarter-finals in seven tournaments.
