Prior to filming, the actors portraying patients studied films of Dr. Oliver Sacks's actual post-encephalitis patients, and Robert De Niro and Robin Williams spent time with Sacks in the hospital observing him and his patients.
For the movie Robert De Niro filmed a scene with "Lillian T.", the only surviving patient from Oliver Sacks' book, "Awakenings". She was also said to have been the most outspoken patient in the 1973 documentary about the patients, also called "Awakenings".
When filming the scene where Dr. Sayer and the security guards attempt to restrain Leonard, Robin Williams accidentally hit Robert De Niro in the face with his elbow, breaking De Niro's nose. De Niro later commented that his nose had been broken before, in the opposite direction, and this injury actually straightened it back out.
The name that Leonard spells out on the Ouija board is German poet Rainer Maria Rilke, and the poem that Dr. Sayer quotes in the arboretum is "The Panther."
Penny Marshall at first wanted Bill Murray to play Leonard Lowe, who was interested in the project, but she decided against it because she didn't want audiences expecting a comedy.
At one point a film Steven Spielberg considered directing, before passing it on to Penny Marshall. The time he spent on the project did yield one useful outcome for him: Steven Zaillian's script took several short chapters, each about different patients, and put them together into a linear whole. This brought Zaillian to Spielberg's attention, and he offered Zaillian the similar task of adapting Schindler's List, which ended up winning Oscars for both of them.