The show is centered on the life of an Italian-American everyman named Raymond Barone, a sportswriter for Newsday living with his family on Long Island. Beleaguered, diffident and dryly sarcastic, Raymond takes few things seriously, making jokes in nearly every situation, no matter how troubling or serious. He often avoids responsibilities around the house and with his kids, leaving this to his wife, Debra.

Raymond and Debra have a daughter Ally (Alexandra) and twin sons Michael and Geoffrey (originally Matthew and Gregory in the pilot). The Barone children are regular characters but not a major focus. Raymond's parents, Marie and Frank, live across the street with their older son Robert (who, later in the series, has his own apartment). All Barone relatives frequently make their presence known to the annoyance of Raymond and Debra. Although she loves them, Debra's justifiable complaints about Raymond's overbearing family serve as one of the show's comedic elements. Out of the three unwanted visitors, Debra is particularly intimidated by Marie, an insulting, controlling, manipulative (though ultimately caring) woman who criticizes Debra passive-aggressively and praises Ray, clearly favoring him over other son "Robbie," whose birth necessitated her marriage (a fact revealed in the episode "Good Girls").

Raymond typically falls in the middle of family arguments, incapable of taking any decisive stand, especially if it might invoke his mother's disapproval. Robert, a miserable gentle giant, jealous of his younger sibling's position as favorite son and also of the success his brother has achieved both professionally and personally, is Ray's biggest rival. Robert and Raymond frequently argue like overgrown children, focusing much of their energy on picking on or one upping each other, although deep down they love each other dearly.

Frank Barone is a fiery retiree prone to directing insults and merciless put-downs at any and all targets. Largely an absentee father when the boys were growing up, Frank buries his feelings and rarely yields to sentiment. As the series progresses, however, several episodes demonstrate that the senior Barone loves his family immensely. Unlike everyone else, Frank has no problem comically criticizing Marie and often comes to Debra's defense whenever Marie comments disparagingly about their daughter-in-law.

Raymond and Debra's marriage is fraught with conflicts. Raymond prefers sports television over discussions with Debra on marital matters. Raymond works full-time, as his father had, leaving most child-rearing responsibilities to his wife; and he is often forced to help around the house. One of the show's recurring elements finds the couple having a long discussion in bed each night before going to sleep.