Seidelman was raised in a suburb of Philadelphia, the oldest daughter of a hardware manufacturer and a Teacher. She graduated from Abington Senior High School in 1969, and went on to study fashion and arts at Drexel University in Philadelphia. After taking a film appreciation class where she was inspired by the French New Wave, particularly the films of Jean-Luc Godard and François Truffaut, as well as Ingmar Bergman, she switched her focus to filmmaking.

Seidelman was inspired early on by European Directors Lina Wertmüller and Agnes Varda, who she studied in college in the 1970s—a time when there weren’t a lot of women Directors in the American film industry. The early feminist movement of the 60s and 70s, as well as the personal filmmaking style of the French New Wave, and Directors Jean-Luc Godard, François Truffaut and John Cassavetes were also early influences. Seidelman is a fan of Billy Wilder for his social observation, drama and humor.

In Smithereens, set in the early 1980s, the trope of the plucky heroine trying to make it in the music world is upended by teenaged Wren’s goal to become famous despite having no applicable creative talents. Plastering fliers of her face around the city, Wren’s a precursor of the "famous for being famous" personalities of the Internet age. Seidelman says that Wren’s story "is about something broader: the fragmented nature of life in the 80's. It could have taken place in other settings."

In 1982, Seidelman made her feature-film debut with Smithereens, a bleak and darkly humorous look at New York City's downtown Bohemian scene of the 1980s. It was shot on 16mm for $40,000 on location, at times "guerrilla style" on the streets and in the subways of New York. Smithereens captured the look of the post-punk music scene and was the first American independent film to be selected for competition at the Cannes Film Festival. With recognition from Cannes, Seidelman became a member of the first wave of 80s-era independent filmmakers in the American cinema.

Seidelman has lived in New York City with her partner, Screenwriter and Producer Jonathan Brett since 1986. Their son Ozzy is a Producer and video Editor.

Nora Ephron, who she collaborated with in 1987 for Cookie, was a role model as a Writer and Director who was able to combine family life with a successful film career. Among contemporaries, Seidelman notes the cerebral stories of the Coen Brothers, mid-career Woody Allen, early Martin Scorsese and the films of Jane Campion are all favorites. She’s drawn to Directors with distinct, slightly "outsider" points of view.

In the 1990s and 2000s Seidelman garnered success as a television Director, helming the pilot of Sex and the City, which involved some casting and developing the look and feel of the show. Seidelman thought the pilot script by Darren Star was bold, presenting then-taboo subject matter with humor, saying, "It was the first time that a TV show featured women talking about things they really talk about in private." She directed subsequent episodes during the show's first season.

In 1994 Seidelman and Screenwriter Jonathan Brett received an Academy Award nomination for a short film they co-wrote and co-produced called The Dutch Master. The film was part of the series "Erotic Tales" produced by Regina Ziegler and was screened at both the Cannes Film Festival and Telluride Film Festival. In the same year Seidelman was a member of the jury at the 44th Berlin International Film Festival.

In 2001, Seidelman returned to feature films with Gaudi Afternoon, a gender-bending detective story set in Barcelona, starring Judy Davis, Marcia Gay Harden, Juliette Lewis and Lili Taylor. The screenplay by James Myhre was based on the book "Gaudi Afternoon: A Cassandra Reilly Mystery" by Barbara Wilson.

Her 2005 film Boynton Beach Club was based on an original idea by her mother, Florence Seidelman, who while living in south Florida had gathered true stories of senior citizens who were suddenly back in the "dating game" after the loss of a spouse. It's one of the first movies to deal with sexuality and the aging Baby Boomer generation and had a theatrical run and acclaim at U.S. film festivals. The ensemble cast features studio veterans Brenda Vaccaro, Dyan Cannon, Sally Kellerman, Joseph Bologna, Michael Nouri and Len Cariou.

Seidelman's next film Musical Chairs, opened in limited release in 2011. The story is set in the South Bronx and Manhattan and revolves around a couple taking part in a wheelchair ballroom dancing competition after the woman becomes disabled. The film had its premiere at Lincoln Center's Dance on Camera Festival and played at the New York International Latino Film Festival, the Miami International Film Festival, and the Havana International Film Festival, among others.

Seidelman's 2013 film The Hot Flashes is about middle-aged women living in small-town Texas, all former 1980s basketball champs, reuniting to challenge the current girls' high school team to raise funds for a breast-cancer treatment center. It stars Brooke Shields, Daryl Hannah, Wanda Sykes, Virginia Madsen, Camryn Manheim, and Eric Roberts.

A magic club is also a feature of Gaudi Afternoon where asexual Cassandra, through her attraction to openly bisexual Hamilton—an amateur magician—acknowledges her own sexual awareness. Antoni Gaudí’s eccentric, sensual architecture is the scenic backdrop to Cassandra’s deeper involvement with an alternative family and their young daughter, which ultimately brings about change in her personal life.

A diverse cast of Dancers perform in Musical Chairs, where Armando and Mia’s relationship develops within the world of competitive wheelchair ballroom dancing—a dance form popular in Europe and Asia, but mostly unknown in the U.S. The dance troupe, outsiders in the world of feature-film, include a transgender woman and an Iraqi veteran, highlighting dance as a form of self-expression available to everyone. Laverne Cox, who is transgender, has said that playing Chantelle, a disabled African American transgender woman, in a feature film was a career milestone.