O'Rourke has captured national attention and set a Senate fund-raising record with $38 million in third-quarter donations, more than triple Cruz's.
Democrats nationally have seen the race as a chance at one of the two seats they need to win in congressional elections on Nov. 6 to take a majority in the Senate and more effectively counter President Donald Trump.
But a CNN poll published on Tuesday showed the first-term incumbent Cruz with a 52 percent to 45 percent lead, suggesting national enthusiasm about O'Rourke reflected in media profiles and donations may not be so strong in Republican-leaning Texas, which has not elected a Democrat to the Senate in three decades.
That leaves the San Antonio debate, which will be broadcast live throughout the state, as a key opportunity for former punk rocker O'Rourke to convince Texans of his message.
Cruz has painted O'Rourke, who favors a path to citizenship for illegal immigrants, opposes building a wall along the border with Mexico, and supports some gun-control measures, as too radical for Texas.
Cruz was due to get another dose of support from former presidential primary rival Trump next Monday when the president headlines a Houston campaign rally for Cruz and other Texas Republicans.
O'Rourke has blasted Cruz for supporting massive deportations of illegal immigrants. He has also criticized Cruz for supporting Trump's trade policies, which he said have hurt the Texas economy.
The momentum may have turned in Cruz's favor since the two squared off in Dallas last month, against the backdrop of the debate over Trump's nomination of Brett Kavanaugh to the Supreme Court.
At the time, Cruz argued for swift confirmation of Kavanaugh while O'Rourke joined a chorus of Democrats calling for an FBI investigation into accusations that Kavanaugh sexually assaulted another student while he was in high school.
Following raucous hearings, Kavanaugh was confirmed early this month in a 50-48 vote that firmly solidified the court's 5-4 conservative majority.
(Reporting by Scott Malone, Editing by Rosalba O'Brien and Tom Brown)