Obviously, since this is an Andy Pafko Collector blog, I will start out with the 1952 Topps Andy Pafko card which plays a role in the 2010 film Cop Out starring Bruce Willis and Tracy Morgan.
Bruce Willis is plays a cop that needs to come up with $48K to pay for his daughter's wedding, in order to get that money he needs to sell his 1952 Pafko. The card is shown in several shots of the movie and is even talked about as being in "Gem Mint" condition. I won't ruin the movie for you but I'll tell you that the card ends up in less than mint condition.
Alan Alda of M*A*S*H fame along with Ferris Bueller's and
War Games star Matthew Broderick star in Diminished Capacity, a 2008 film about dealing with Alzheimer's. Alan Alda's character is trying to sell a T206 Frank Wildfire Schulte. The two end up at a Chicago card show and run into an unsavory dealer who looks a lot like the Mr. Mint guy you see in hobby publications.
Although not a very popular film, 1993's Ruby Cario (a.k.a Deception) had an all-star cast featuring Andie MacDowell, Liam Neeson and Viggo Mortensen. Several baseball cards make an appearance in this film and actually serve as part of the plot. Mortensen's character disappears which causes MacDowell to try and find out what happened. She finds a stack of baseball cards which have several elements on the backs of the cards circled or otherwise annotated which lead her around the globe. It took me some pausing to figure out which cards played a role but they are the following: 1965 Topps Bill Maseroski #95, 1967 Topps Orlando Cepeda #20, 1985 Topps Onix Concepcion #697, 1959 Topps Don Mueller #368, 1960 Topps Bobby Thomson #153, 1973 Topps Milt Pappas #70, 1961 Topps Rocky Nelson #304, 1962 Topps Harvey Haddix #67 and finally, 1981 Topps Manny Sanguillen #226. I'm not entirely sure why these cards were picked for the film, perhaps that was in the director's shoebox? Mortensen's character does mention being a Pittsburgh Pirate's fan so that explains a few of them. Although I didn't like the ending, the idea of baseball cards being used as clues in a movie is a winner with me.
It wasn't shown on screen but in the film Enchanted, a couple is seen arguing in the presence of a divorce lawyer played by Patrick Dempsey. The couple is discussing who will get custody of a 1954 Hank Aaron RC.