Waheeda Rehman started her career in films in 1954 and her first successful films were the Telugu films Jayasimha (1955), Rojulu Marayi (1956) and Tamil film Kaalam Maari Pochu (1955). It was M.G.Ramachandran who offered her the song "Salaam Babu" in Modern Theatres production of the Tamil film Alibabavum 40 Thirudargalum (1956 film).

Rehman was in her teens when her Father died. Her dream was to become a Doctor, but, due to her family's circumstances and her mother's illness, she abandoned her goal. In order to help her family, she hit the silver screen with Telugu films; Jayasimha (1955), followed by Rojulu Marayi (1955) and a Tamil film Kaalam Maari Pochu (1956). It was in Vijaya-Suresh's Ram aur Shyam (a remake of the Telugu movie Ramudu Bheemudu) in 1967 that she acted again under the direction of the topnotch Telugu Director Tapi Chanakya, who incidentally directed her movies Rojulu Maaraayi (in Telugu) (1955) and Kaalam Maaripochu (in Tamil) (1956).

Waheeda Rehman established a great working relationship with Dev Anand, and together as a pair had number of successful films to their credit. The box office hits of the pair include CID (1956), Solva Saal (1958), Kala Bazar (1960), Baat Ek Raat Ki (1962) and Guide (1965); box office duds were Roop Ki Rani Choron Ka Raja (1961) and Prem Pujari (1970). She reached her peak with Guide (1965) and was much in demand. Rehman was cast as Gulabi in Satyajit Ray's Bengali film Abhijan in 1962. She worked in the comedy film Girl Friend in 1960 with Kishore Kumar. She was offered the lead actress's role in films even opposite actors junior to her by experience like Dharmendra, but they flopped. But she continued to taste success in the late sixties when she was paired with well established stars. She delivered hits opposite Dilip Kumar in three successive years; Dil Diya Dard Liya in 1966, Ram Aur Shyam in 1967 and Aadmi in 1968 and some box office duds but critically acclaimed films with Rajendra Kumar; Palki, Dharti and Shatranj; two films opposite Raj Kapoor; Ek Dil Sau Afsane and the acclaimed Teesri Kasam, which was the debut film of Basu Bhattacharyya; a few films opposite Biswajeet such as Bees Saal Baad and Kohra; this helped her continue to get lead roles in the early seventies. Her career's biggest hit Khamoshi came in 1970, opposite Rajesh Khanna.

Her career continued throughout the 1960s, 1970s, and 1980s. She won the Filmfare Best Actress Award for her roles in Guide (1965), where she hit the peak of her career, and Neel Kamal (1968), but despite excellent offbeat roles in subsequent films, including a National Award winning performance in Reshma Aur Shera (1971), some of the films failed at the box office. Seeing her films being successful, Waheeda decided to experiment with roles at this stage of career. She accepted Reshma Aur Shera, opposite her old co-star Sunil Dutt, with whom she had previously in the sixties had hits such as Ek Phool Char Kaante, Mujhe Jeene Do, Meri Bhabhi and Darpan. Her performance was appreciated by critics, but the film failed at the box office. But Waheeda continued to experiment with roles and accepted the offer to play a mother to Jaya Bhaduri in Phagun (1973). This, she regards the mistake of her career, as after this film flopped, suddenly people started offering her motherly roles to heroes.

From the mid-seventies, Waheeda's career as lead heroine ended and her career as character actor began. At around this time, Kamaljit, who starred opposite her in Shagoon (1964), proposed and they got married in 1974. After her appearance in Lamhe (1991), she retired from the film industry for 12 years.

After her marriage to Shashi Rekhi (screen name Kamaljeet) on 27 April 1974, she shifted to a farmhouse in Bangalore. She has two children named Sohail and Kashvi, who are Writers. On 21 November 2000, her husband died following a prolonged illness. She moved back to her ocean view bungalow in Bandra, Mumbai where she currently lives.

In her new innings from the seventies, her successful films where she played pivotal roles include Kabhi Kabhie (1976),Trishul (1978), Jwalamukhi (1980), Namkeen and Namak Halaal (1982), Mashaal (1984), Chandni(1989) and Rang De Basanti(2006). She played the central character in the Mahesh Bhatt directed film Swayam that starred Akash Khurana and Anupam Kher. She also appeared in a tele-series being directed by Gulzar.

In recent years she made a comeback playing elderly mother and grandmother roles in Om Jai Jagadish (2002), Water (2005), Rang De Basanti (2006), 15, Park Avenue and Delhi 6 (2009) which were all critically acclaimed.

In October 2004, a Waheeda Rehman film retrospective was held at the Seattle Art Museum and the University of Washington where Waheeda participated in spirited panel and audience discussions on her most memorable films; Pyaasa, Teesri Kasam and Guide - although her most successful film is still considered to be Khamoshi, with costar Rajesh Khanna.