In clinical trials, oral supplementation with nicotinamide riboside (NR) fails to increase muscle mitochondrial respiratory capacity and insulin sensitivity but also does not increase muscle NAD⁺ levels. This study tests the feasibility of chronically elevating skeletal muscle NAD⁺ in mice and investigates the putative effects on mitochondrial respiratory capacity, insulin sensitivity, and gene expression. Accordingly, to improve bioavailability to skeletal muscle, we developed an experimental model for administering NR repeatedly through a jugular vein catheter. Mice on a Western diet were treated with various combinations of NR, pterostilbene (PT), and voluntary wheel running, but the metabolic effects of NR and PT treatment were modest. We conclude that the chronic elevation of skeletal muscle NAD⁺ by the intravenous injection of NR is possible but does not affect muscle respiratory capacity or insulin sensitivity in either sedentary or physically active mice. Our data have implications for NAD⁺ precursor supplementation regimens.