Season 1 featured 18 episodes and began airing on September 19, 2007. However, due to the 2007-2008 Writers Guild of America strike, only 13 episodes were produced from the planned 22, but once the strike ended, the network announced five more episodes to be produced, and finally the season concluded on May 19, 2008. The season premiered with 3.5 million viewers,^[7] and ended with 3.00.^[8] Although the ratings were low the network renewed the show for second season due their aiming on male and female demographics on age 18-34.

In the beginning of the first season, the episodes focus on why Serena initially left. It is soon discovered that she felt an overwhelming guilt for sleeping with her best friend Blair's boyfriend Nate Archibald behind Blair's back. However, as the season progresses, Georgina Sparks, a new character with malicious intentions, comes back to haunt Serena. It is soon discovered that the real reason Serena left was because one night she and Georgina were hanging out in a hotel room after a night of drinking and partying. Things soon got out of hand when the man they were with asked for his cocaine and Serena gave the drugs to him. Immediately after, the man began having a seizure and the two girls panicked and ran away. Serena felt obligated to at least call 911 for help, and as she ran across the street in hiding, she saw that the man they were with had died. This is the full reason why Serena left because in the same night she had slept with her best friend's boyfriend and killed a man. Part of the main story arc also involves Serena's relationship with Dan Humphrey, an outsider from Brooklyn who she begins to date but has a rocky road with because of their different family backgrounds.

Other storylines include Blair breaking up with Nate and falling for his best friend Chuck Bass, which leads to her dethroning as Queen Bee; Jenny's training to become the next Queen Bee lead by Blair, which contribute to both of them later in the season beginning war for the throne; Nate's family problems; Lily's marriage with Bart Bass; Rufus' troubled marriage; Dan's relationship with Serena, which is interrupted by his former love Vanessa Abrams; and the friendship of Chuck and Nate.