Tissue inertia is rarely considered in our understanding of skeletal muscle behaviour. Studies have shown that larger muscles perform less mass-specific mechanical work during cyclic contractions due to their greater inertial mass; however, it is not known how this greater mass alters the metabolic cost and efficiency of contraction. In this study we examined the effects of tissue inertia on muscle metabolic cost and efficiency during cyclic contractions. To accomplish this, we simulated work-loop contraction cycles of a mass-enhanced Hill-type muscle model with bursts of excitation timed to sinusoidal muscle length changes. We additionally explored how the behaviour of a tendon alters the relationship between tissue inertia and muscle and muscle-tendon unit mass-specific mechanical work, metabolic cost, and efficiency per cycle by adding a tendon of varying stiffness in series with the muscle model. We found that larger muscles with greater tissue inertia are less efficient than smaller muscles, primarily due to their lower mass-specific mechanical work output. We also found that accounting for a tendon decreased the mass-specific work and efficiency penalty of larger muscles, but this depended on the stiffness of the in-series tendon and the timing of the muscle excitation relative to the sinusoidal length changes. The results of this study highlight the importance of accounting for muscle tissue inertia when predicting whole muscle and muscle-tendon unit behaviour.