"I believe you always deserve to hear the truth from your president. We have to slow the growth of this virus. We owe it to the doctors and the nurses and the frontline workers," Biden said.
He urged people to forgo big family gatherings, wear protective masks and maintain social distancing.
"I know we can and we will beat this virus," Biden added, acknowledging that Americans are feeling pandemic fatigue. "Life is going to return to normal. I promise you. This will happen. This will not last forever."
The Democratic former vice president has vowed to make tackling COVID-19 a top priority after taking office on Jan. 20, having accused Trump during the campaign of panicking and surrendering in the face of a public health crisis.
Since winning the Nov. 3 election, Biden has offered a message of national healing and reconciliation after Trump's tumultuous term while the Republican president still refuses to concede and falsely claims the election was stolen.
Public health officials have urged Americans to stay at home for Thursday's holiday and avoid large gatherings that could spread the virus.
Biden said he planned to spend Thanksgiving with his wife, Jill, and their daughter and son-in-law.
JOE BIDEN: My fellow Americans, Thanksgiving is a special time in America, a time to reflect on what the years brought and think about what lies ahead. We fought nearly a year-long battle with a virus that has devastated this nation, has brought us pain and loss and frustration.
We still have months of this battle ahead of us. For those who've lost a loved one, I know that this time of year can be especially difficult. Believe me, I know. I remember that first Thanksgiving-- the empty chair, the silence. It takes your breath away. It's really hard to care. It's hard to give thanks. It's hard to even think of looking forward.
I know how hard it is to forgo family traditions. But it's so very important. Our country's in the middle of a dramatic spike in cases. Many local health systems are at risk of being overwhelmed. That's the plain and simple truth. Nothing made up. It's real.
And I believe you always deserve to hear the truth, hear the truth from your president. We have to try to slow the growth of this virus. We owe it to the doctors and the nurses and other frontline workers.
Every decision we make matters. Every decision we make can save lives. None of these steps we're asking people to take our political statements. Every one of them is based on science, real science. Don't let yourself surrender to the fatigue, which I understand it is real fatigue.
I know we can and we will beat this virus. America is not going to lose this war. We'll get our lives back. Life is going to return to normal. I promise you, this will happen. This will not last forever. So yes, it's been a really hard year, particularly hard for over 250,000 people and their families. But I still believe we have much to be thankful for.
What should we give thanks for this season? Well, first, let's be thankful for democracy itself. In the middle of a pandemic, more people voted this year than have ever voted in the history of the United States of America. Over 150 million people cast a ballot.
Our democracy was tested this year. And what we learned is this. The people of this nation are up to the task. In America, we have full and fair and free elections. And then we honor the results.
Folks, from the Biden family to yours, wherever and however you may be celebrating, we wish you a Happy Thanksgiving. May God bless you, and may God protect our troops. Happy Thanksgiving.