Clinton, D-N.Y., is asking the Federal Trade Commission to probe how users of the game can access "graphic pornographic and violent content" for the game from the Internet.
In a letter dated Thursday to FTC chairwoman Deborah Platt Majoras, she also urged the agency to examine whether the game's rating of "M" for mature should be changed to an "Adults Only" rating.
The Entertainment Software Ratings Board, a self-regulatory ratings arm of the game software industry, is already investigating the issue.
New York's junior senator said it is time for the federal government to step in.
"There is no doubting the fact that the widespread availability of sexually explicit and graphically violent video games makes the challenge of parenting much harder," Clinton said in her missive seeking an FTC investigation.
The senator is also pushing legislation that would make it harder for young kids to get access to such content.
Even before her election to the Senate, Clinton spoke out against the amount of sexual and violent content available to children.
In March, Clinton delivered a speech to the Kaiser Family Foundation in which she called media sex and violence "a silent epidemic" among children, and sought federal research into how exposure to such graphic content affects young minds.
In that speech to media experts and child advocates, she singled out "Grand Theft Auto" as particularly harmful, saying it "has so many demeaning messages about women and so encourages violent imagination and activities and it scares parents.... They're playing a game that encourages them to have sex with prostitutes and then murder them. You know, that's kind of hard to digest."