As a junior high student in Westchester County, New York, Raphael became intrigued by broadcasting and started her career with a local school news program. Over the course of some twenty years, she traveled from Puerto Rico to Florida to New York where she held various jobs. Persisting despite defeat, her spirits were buoyed by her second husband, Karl Soderlund, who acted as Raphael's booster, promoter and manager, getting her a new job each time she was fired. There were admittedly lean times where the family was forced to live in their automobile, eating ketchup on crackers and when Raphael even went on public assistance. But she persevered and finally hit the big time in 1983 when she began hosting a half-hour talk show "In Touch with Sally Jessy Raphael" from KSDK-TV in St Louis, Missouri. Multimedia took the show national within six months and within four years, the show's headquarters were relocated to the East Coast. Her talk show is often a multi-hankie affair, and the host exudes an "I care" attitude, which she often carries off-screen, offering her traumatized guests help outside the framework of the show. Raphael has been particularly successful with reuniting lost loved ones, but has also brought more outre topics to national TV. She won a 1989 Daytime Emmy Award as Outstanding Talk Show Host (the show won in 1990).

Raphael's fame brought her occasional cameos as herself in films, such as "Resident Alien" (1990) and "The Addams Family" (1991), as well as in the TV-movie "Fatal Flaw" (ABC, 1989). In 1996, Raphael made her TV acting debut playing a judge who sternly sentences a murderous Fred Savage in "No One Would Tell" (NBC). She has branched out to producing with the 1997 CBS TV-movie "Ken Follett's 'The Third Twin'".