I have two, large, mature Blue Spruce trees. Over the years, the lowest branches have mostly become deadwood. In addition, weeds have taken root all throughout the base area of the tree, extending out to the edge of the longest branches. It's impossible to cut these weeds down with the lowest branches in the way, so I'm considering cutting just the very lowest branches down in order to have access to the weeds, some of which climb up the entire tree & do damage.

Is this ok to do without damaging the Blue Spruce?

IMO, I'd cut the lower branches. Sounds like you'd do doing yourself and the tree a favor. Gene

Thanks for advice, I will!