Will's relationship with his parents was always prone to issues, particularly his father, who, though outwardly supportive of Will's lifestyle, was uncomfortable with his son's sexuality for years. In season eight, the two had a fight in which George confessed he wished Will weren't gay. A few days later, having not spoken with Will since the fight, George died of a heart attack.

Will has had romantic "relationships" with three women: Grace; his high-school girlfriend Claire (Megyn Price); and Diane (Mira Sorvino) — the woman with whom he had a one-night stand after he and Grace broke up. Diane is the only woman with whom Will has ever had sex.

At the beginning of the series, Will's most successful relationship with a man was said to have been with long-term boyfriend Michael (Chris Potter), whom he was together with from 1989, to November, 1996. In the 2004-2005 season, however, he became involved in a serious relationship with a NYC police officer named Vince D'Angelo (Bobby Cannavale). Their relationship was put on hiatus after Vince, who lost two jobs in a row because he couldn't resist trying on gloves while on duty, needed to take some time off from the relationship. Towards the end of the final season (2006), the two reunited after Will's father's death. In the series finale, it was revealed that he and Vince were raising a son named Ben. Thus, by the end of the series, Will and Vince's relationship has been strong for nearly 22 years.

Much of the comedy on the show is at Will's expense, and many of the characters play off his many unsuccessful relationships between Michael (and sometimes including the failure of that relationship) and Vince.