Hi Scotty,
The 2 things I do when working with plexi are if drilling a hole I tape over the area (top and bottom). I use very high speed on the drill press and very low downward pressure. If cutting a hole I tape the area to be cut (top and bottom), then sandwich (clamp) the plexi between 2 pieces of wood then make my cut. Plexi is a bitch to work with and this works about 75% of the time. Hope this helps you out.
Maddawgs

scotty when drilling plexi always use a backing....I use tape for tiny holes and tape with a plywood backing for larger holes and as Maddawgs said very low pressure! For large holes (>1 in) I back it up as above and use a specialized tool, don't know its name but it has a small drill in the axis for a center guide and an adjustable swing cutting arm that turns around periphery, mount in drill press and go slow. It works perfect

Hi Scotty,
It is better if you cut all at the same time. Helps to stop chip out and cracking, plexi loves to do both. Just draw a cardboard template for the piece you want to make with the hole locations. Use that to cut the plywood sandwich pieces Just the outside dimensions, not the holes . Then just transfer the hole locations from your cardboard template onto the plywood. Tape the top and bottom of the areas you will drill or cut on the plexi, sandwich in between the plywood with good clamping pressure, make your cuts and hope for the best. I am in no way a pro but this does work about 75% of the time. I always try to have 2x the plexi I need for the job because for me plexi is a bitch to work with
Maddawgs

If I am cutting panels and need smooth accurate dimensions I cut the panels 1/4" oversize and then run them over my jointer to clean and bring down to final dimension. or I use a router with a laminate trim bit and a guide clamped down if the material is thinner than 1/4" thick. I use a plunge router and template for cutting most of my holes but they are usually bigger holes than you want. I think you could do it with the router though.