Preheat oven to 400 degrees F. Butter a 9x13-inch casserole dish. Heat a large pot of water over high heat for the pasta; cover.
Prepare the Shrimp: In a 10-inch skillet, melt the butter over medium heat. Add the shrimp and Cajun seasoning and cook, stirring occasionally, until it is all pink and cooked through. Remove the pan from the heat and set aside.
Prepare the Macaroni and Cheese: Add the pasta to the boiling water and cook the pasta according to the box directions for al dente pasta (if your box doesn't specify al dente, cook it for 1 to 2 minutes shorter than the time called for - it shouldn't be cooked the whole way through). When the pasta is finished cooking, drain it in a colander.
While the pasta is cooking, make the sauce. In a large saucepan, melt the butter over medium heat. Once the butter has melted, whisk in the flour and cook for about 1 minute, until the flour starts to brown a bit and smells nutty, whisking constantly. In a slow, steady stream, whisk in the milk. Allow the sauce to come to a simmer.
Once the sauce comes to a simmer, stir in the Pepper Jack and cheddar cheeses, adding a handful at a time and stirring with a wooden spoon until completely melted before adding the next handful. Season with the Cajun seasoning, salt and pepper, and turn off the heat.
Add the cooked, drained pasta and shrimp to the sauce. Stir with a wooden spoon until everything is completely combined and evenly distributed. Pour the mixture into the prepared casserole dish.
Prepare the Topping: In a small bowl, mix the melted butter with the Panko bread crumbs, tossing with a fork until the entire mixture is evenly moistened.
Sprinkle the macaroni and cheese with the shredded cheeses. Sprinkle the bread crumb mixture on top of the cheese.
Bake until browned and bubbly, about 15 to 20 minutes. Allow to sit for 10 minutes before serving.