Low skeletal muscle mass is highly prevalent in older cancer patients and affects 5% to 89% depending on the type and stage of cancer. Low skeletal muscle mass is associated with poor clinical outcomes such as post-operative complications, chemotherapy toxicity and mortality in older cancer patients. Little is known about the mediating pathophysiological mechanisms. In this review, we summarize proposed pathophysiological mechanisms underlying the association between low skeletal muscle mass and poor clinical outcomes in older cancer patients including a) systemic inflammation; b) insulin-dependent glucose handling; c) mitochondrial function; d) protein status and; e) pharmacokinetics of anticancer drugs. The mechanisms of altered myokine balance negatively affecting the innate and adaptive immune system, and altered pharmacokinetics of anticancer drugs leading to a relative overdosage of anticancer drugs are best-substantiated. The effects of glucose intolerance and circulating mitochondrial DNA as a consequence of low skeletal muscle mass are topics of interest for future research. Restoring myokine balance through physical exercise, exercise mimetics, neuro-muscular activation and adapting anticancer drug dosing on skeletal muscle mass could be targeted approaches to improve clinical outcomes in older cancer patients with low skeletal muscle mass.