The proceedings, which begin Tuesday, will be broadcast live on television and all eyes will be focused on the impartiality of the Spanish Supreme Court. Over 600 journalists from 150 domestic and foreign media are accredited.
"It's the most important trial we have had in democracy", Supreme Court president Carlos Lesmes told reporters on February 1, referring to the return to democracy in Spain after dictator Francisco Franco's death in 1975.
Catalan separatists have dismissed the trial as a "farce" which is politically motivated.
But for many Spaniards who looked on in disbelief as the region's then executive tried to break from the country in October 2017, the trial is indispensable.
Thousands attend Madrid demo against Catalan independence.
Spain does not try suspects in absentia for major offences.
The conflict with Catalonia has been festering ever since, with a regional election on December 21, 2017, showing that the 7.5 million residents of Catalonia remain divided by the secession question. He faces up to 25 years in jail.
The massive rally comes just two days before the trial of 12 Catalan independence leaders kicks off. He and eight other defendants have spent over a year in pre-trial custody because they were considered to be flight risks.
Nine defendants have been charged with rebellion, with some also accused of misuse of public funds.
Spain is bracing for the nation's most sensitive trial in four decades of democracy this week, with a dozen Catalan separatists facing charges including rebellion over a failed secession bid in 2017.
Under Spanish law, rebellion is defined as "rising up in a violent and public manner".
Among the many witnesses will be Mariano Rajoy, who was Spanish prime minister at the time of the independence vote and its aftermath.
The leaders of Spain's main three right wing parties - the conservative Popular Party (PP), centre-right Ciudadanos (Citizens) and far right Vox, had called the demonstration after the government's proposal to appoint a rapporteur in talks amongst political parties created to come up with agreement over the problem.
Mr Sanchez, who came to power in June with the support of Catalan nationalist parties, defended his government's attempts at dialogue with Catalonia.
The government is squeezed on both sides of the Catalan issue: Deputy Prime Minister Carmen Calvo said on Friday the talks were on track to fail because Catalan pro-independence groups had rejected the government's proposed framework.
Sanchez's minority government relies on the support of Catalan separatist parties to approve its 2019 budget.
Even though Mr Sanchez has said he wants to see out the legislative term to 2020, a failure to win a budget vote will crank up the pressure on him to call for an early election.