When Alex has a brief conversation with Dr. Fitch in "Hell's Descent", the weird sounds in the background are from a scene in Stephen King's film Eso (1990), directed by Tommy Lee Wallace.
All but some of the streets in Shepherd's Glen are named after famous horror/suspense movie kings, including: Wes Craven (Nightmare on Elm Street), Stanley Kubrick (The Shining; Clockwork Orange), John Carpenter (Halloween; The Fog; The Thing remake), Adrien Lyne (Jacob's Ladder), William Friedkin (The Exorcist), and Clive Barker (Hellraiser).
The trucker in the beginning is Travis Grady, from Silent Hill: Origins.
The opening sequence is a possible reference to the hospital sequence of Adrian Lyne's film Alucinaciones del pasado (1990). Konami has been known to reference "Ladder" in almost all of the Silent Hill installments.
The first Silent Hill game to take place in a more recent time period than the previous games which ranged from 30 years to 3 years ago.