O'Rourke criticized Cruz for associating with someone who would say such things about his family. "He's dishonest, and it's why the president called him Lyin' Ted, and it's why the nickname stuck-because it's true".
Cruz decried O'Rourke's "extreme views" on abortion.
But O'Rourke will need a comeback in conservative Texas, which has not elected a Democrat to statewide office since 1994.
Cruz and O'Rourke, who first debated September 21 in Dallas, may have sparred for the last time before Election Day when they took the stage in San Antonio. "It's a campaign based on fear", O'Rourke said, "It's the same person who shut down the government of the United States of America for sixteen days, perhaps because he though too many people had too much healthcare".
Both candidates lobbed attacks throughout, taking more aggressive stances as the race enters the final stretch and Democrats try to keep their fledgling hopes of re-taking the Senate alive despite a hard host of races in many states President Donald Trump won handily in 2016.
Cruz said O'Rourke was eager to begin impeachment proceedings against Trump that would lead to a partisan circus.
On Tuesday night, the Democrat went on the attack with charges such as, "Ted Cruz is for Ted Cruz".
"Watched the debate last night & Beto O'Rourke, who wants higher taxes and far more regulations, is not in the same league with Ted Cruz & what the great people of Texas stand for & want". O'Rourke accused Cruz of not doing enough to stand up to Trump when it came to Russian Federation and that the state needs a "full-time senator" rather than someone who concentrates on running for president.
In response to a question about the #MeToo movement, O'Rourke said Cruz "inexplicably" voted against the Violence Against Women Act, saying the senator was "all talk and no action". You were all talk and no action.
Cruz closed by again highlighting his policy differences with O'Rourke on immigration, health care and a host of issues, saying he is also offering a positive vision for the state of Texas.