"We get involved, we take a lead, we make a difference, we get things done," he said.
"If we left, our neighbors will go on meeting and making decisions that profoundly affect us, affect our country, affect our jobs -- but we wouldn't be there. They would be making decisions about us, but without us."
Cameron made a direct appeal to voters of his and older generations "to think about the hopes and dreams of your children and grandchildren" as they cast their votes in the national referendum.
He said that belonging to the EU was good for Britain's economy, security and international standing, and warned that a Brexit would be irreversible.
"There is no going back," he said.
Ahead of the critical decision this week, a record number of people have registered to vote in the referendum, according to figures published by the British Electoral Commission on Tuesday.
Just under 46.5 million people registered to vote, exceeding the previous record at 46.4 million for the parliamentary general elections in 2015.
Cameron: 'We are safer in'
Cameron said he knew from experience "that we are safer in Europe than out on our own."
"I've seen firsthand in these dangerous times how we can better cooperate with our friends and neighbors, how we can share information, track terrorists down, bring them to justice," he said.
"How alongside key allies like the French and the Germans, we're more effective at facing down threats and keeping people safe."
He said that belonging to the 28-member union amplifies Britain's power on the international stage, allowing it to promote the values it stands for through the world.
The "Leave" camp argues that Britain is better off out of the dysfunctional EU, claiming a Brexit would allow Britons to take back control of their country.
Neck and neck
With two days left before the historic vote, both camps are making final appeals to voters as they attempt to sway the undecided.
Prominent "Leave" campaigner Boris Johnson, a member of Parliament, and London Mayor Sadiq Khan, a "Remain" advocate, faced off Tuesday night in a two-hour televised debate.
The fiery "Great Debate" took on a sporting match vibe before 6,000 people at London's Wembley Stadium as the two opposing sides clashed over issues such as immigration, international relations and the economy.
Johnson accused the "Remain" camp of running on fear and said a Brexit offered "hope."
"If we vote 'Leave,' we can take back our country," he said to raucous applause. "This Thursday can be our country's Independence Day."
Meanwhile, Khan asked the Leave campaigners what the plan was for an exit.
"What is your plan?" he asked. "How would you make sure the terms of trade with the EU are better than they are now?"
Khan repeated similar words from Cameron's speech earlier in the day, urging voters to "Stay and fight. Don't quit!"
Cameron did not take part in the debate, so his televised address was viewed as a key late pitch to the nation.
Cameron has led the effort to remain in the EU, under improved terms negotiated with European leaders earlier this year, throughout the unusually acrimonious referendum campaign
The "Leave" and "Remain" campaigns, which have been neck and neck in the polls, resumed their activities Sunday following a pause in the wake of last week's shocking killing of lawmaker Jo Cox
, a rising star in the opposition Labour Party.
Polling has consistently shown voters sharply divided on the issue, with a significant group undecided.
Britain's leading political parties also are split, with much of Cameron's strongest opposition coming from members of his own ruling Conservative Party. Britain's press is equally divided on whether to stay or leave.