"Nate, I'm really sorry I left the morning after. I never meant to hurt you. I wish that somehow we could relive that night, because this time I'd know that you love me. And you know that I love you."
-Serena to Nate, The Sixteen Year Old Virgin
Serena and Nate have been close friends since early childhood. Nate lost his virginity to Serena shortly prior to the show beginning, at the Sheppard Wedding, shown in the series premiere. Throughout the series, they continue being best friends. In Season 3 they enter a romantic relationship, but break up in the season finale, Last Tango, Then Paris. Serena ultimately loves Dan and chooses to be with him over Nate. Though it took sometime to reconcile, Nate and Serena remain good friends for the rest of the show. In the finale, Nate attended Dan and Serena's wedding.
In the Gossip Girl novel series, Serena and Nate are on-again, off-again. They lose their virginity to each other in the series prequel, It Had To Be You, during the summer before Serena leaves for boarding school. Once Serena returns, their antics often lead to the break-ups of Blair and Nate. Serena realizes her love for Nate at various points in the series. One of the main reasons stopping their relationship is that their best friend, Blair Waldorf, is also in love with Nate. In the final book, I Will Always Love You, Nate chooses Blair in Part I and then Serena in Part II. In the end, Nate ends up with neither, and Blair and Serena go off together as best friends on vacation.
In the television adaption, Serena is the reason Nate and Blair break up; Serena and Nate slept together at the Sheppard wedding during their sophomore year before the start of Season 1 as juniors. They finally get together in Season 3, but in the season finale, they break up for good.
In the first season, when Serena returns, Nate hopes to give their relationship a real chance. But Serena refuses, not wanting to hurt Blair further after sleeping with Nate. However, Serena still agrees to meet up with Nate to talk with about their current situation.
After Nate promises Blair that he will never see or talk to Serena again after revealing he slept with her, he gives Serena a cold shoulder during Ivy Week. Throughout the season, their friendship mends. Serena dates Dan and Nate dates Vanessa. In the end of season 1, they are seen together as friends welcoming summer.
The second season opens with Nate and Serena pretending to date, to let Serena heal from her break up with Dan and to cover Nate's secret relationship with Catherine Beaton. As the season progresses, both Nate and Serena date other people. Serena briefly gets back together with Dan, and dates Aaron Rose and Gabriel Edwards for a short time. Nate continues his relationship with Catherine, although after awhile, only does so due to her blackmailing him. He also dates Vanessa, but the pair break up due to incompatibility and differences in their interests. Towards the end of the season, Nate gets back together with Blair, but they agree to end their relationship by the time they graduate. Throughout the season, Nate and Serena remain friends.
In the third season, Nate realizes he still has feelings for Serena and attempts to act on them, but stops when Serena has an affair with his cousin Tripp van der Bilt. However, their relationship ends after he leaves an injured Serena alone after a car accident, afterwards which Nate and Serena get together. Nate tells Serena that he has been crazy about her all these years since the Shepherd wedding. They begin 'officially' dating in The Hurt Locket. Gossip Girl dubs the two the "Golden Couple", due to their attractiveness and pure happiness. The majority of their relationship is happy, but different issues test them. Jenny Humphrey still harbors a crush on Nate, and tries multiple times to get between them but fails. Serena's father, William van der Woodsen also comes back into the picture, along with Carter Baizen, and that causes trust issues to arise with Serena and Nate. After Dr. van der Woodsen leaves town after a scandal, Serena leans on Dan for support and the two kiss. The next morning, Jenny sees the two sleeping in his bed and sends a photo to Gossip Girl. Nate sees, and after confronting Dan and Serena, decides to forgive her. However, Serena realized her love for Dan and ends her relationship with Nate, hoping to get back together with Dan, her true love.
In season 4, Serena and Nate aren't romantically involved. It opens with Nate still heartbroken over his break-up with Serena. He and Serena are on speaking terms but not super-friendly. Nate starts dating Juliet, a girl secretly obsessed with taking Serena down. However, Nate soon decides to win Serena back. Serena ends up in a situation where she needs to choose between Nate and Dan. Nate still cares for her but is put off when Juliet pretends to be Serena and kisses both Nate and Dan. Nate clarifies that this is typical Serena behavior and that he is not going to let her pull him back in ever again. Dan disagrees.
In rehab, Serena admits to Dan that she had picked him, that he was the only one she came to kiss.
In the fifth season, Nate and Serena's romantic prospects officially come to an end. On the day of Blair's wedding, Nate tells Dan that he has never had an honest relationship and that the only girls he has chased have been wrong for him.
On the same day, Serena professes her eternal love for Dan Humphrey and tells him that she has always loved him and he is the only one she will always love.
In the finale, Nate is present while Serena marries Dan Humphrey.