Lead attorney Donna Rotunno said prosecutors had created "an alternative universe" in which the "Pulp Fiction" producer was a "monster" who preyed on aspiring actresses, but had not provided any evidence to convict.
"He was innocent when he walked through the door. He was innocent when witnesses started to take the stand. He is innocent as he sits here right now," Rotunno told the New York court.
Weinstein, 67, faces life imprisonment if convicted of predatory sexual assault charges in the high-profile trial that marks a watershed moment in the #MeToo movement.
Since testimony began on January 22, six women have taken the stand to say they were sexually assaulted by Weinstein, allegations the fallen movie mogul denies.
Rotunno reminded the 12 jurors that they are considering charges related to just two women: ex-actress Jessica Mann and former production assistant Mimi Haleyi.
Mann says Weinstein raped her in March 2013 while Haleyi alleges he forcibly performed oral sex on her in July 2006.
"From an overzealous media, from an overzealous prosecution, you are being asked to make an unpopular decision," Rotunno told the jury, asking them "to block out the noise" surrounding the proceedings.
"Never let your emotion cloud your intellect. Use your New York City common sense. It will guide you to the right answer," she added.
The trial has raised complicated issues surrounding consent and abuse of power for the jury of seven men and five women.
Under cross-examination, both Mann and Haleyi acknowledged at least one consensual sexual encounter with Weinstein after the alleged assaults.
Rotunno repeatedly referred to dozens of emails and texts the defense presented during the trial that show the accusers on friendly terms with Weinstein years after the alleged incidents.
"The truth leaves a paper trail," she said, asking the jurors to study the "real-time evidence" not a world created by the prosecution "where women don't have choices."
"In their universe women are not responsible for parties they attend, the men they flirt with... or the jobs they ask help to obtain," Rotunno added, suggesting women used Weinstein to advance their own careers.
She said Mann only decided she had been assaulted after accusations against Weinstein ignited #MeToo in October 2017, adding she had been manipulated by the prosecution.
"I feel sorry for Jessica Mann. She's a victim of the state," Rotunno said.
The lawyer also suggested that the six women who testified would have got themselves tested for sexually transmitted diseases if they had been attacked.
Weinstein faces five counts, including predatory sexual assault, rape and engaging in a criminal sexual act.
Rotunno reminded jurors that to convict the defendant they must be sure of his guilt beyond all reasonable doubt.
"It's not a small doubt, it's not a little doubt," she said.
The prosecution will present its closing arguments on Friday before jurors begin considering Weinstein's fate on Tuesday next week.
They must reach unanimous verdicts on each count. If they are unable, the judge may be forced to declare a mistrial.
A split verdict is possible where Weinstein is convicted of some charges and cleared of others.
Accused of sexual misconduct by more than 80 women, Weinstein faces a separate sex crimes investigation in Los Angeles and is the subject of several civil complaints.