<p>Calpains (CAPN) serve a crucial function in the regulation of NF-κB activity within skeletal muscle by mediating the degradation of IκBα, facilitating NF-κB activation, inhibiting apoptosis through the suppression of c-FLIP, modulating the activity of p65, p52, and p50, and enhancing the expression of its inhibitor, cardiac ankyrin repeat protein, among other roles. Through these coordinated actions, CAPNs fine-tune inflammatory and survival signaling in muscle cells. The lack of CAPNs leads to increased apoptotic myonuclei and a range of pathological conditions, including muscle weakness, impaired regeneration, and enhanced susceptibility to stress-induced damage. The multifaceted role of CAPNs in modulating NF-κB activity in skeletal muscle constitutes a complex and vital aspect of cellular signaling pathways. CAPNs function as both primary and alternative cleavage agents, modifying diverse proteins that modulate NF-κB signaling. This dual role allows CAPNs to act as both activators and modulators of NF-κB-dependent transcriptional responses. The intricate interplay between CAPNs and NF-κB highlights the importance of maintaining appropriate regulation and equilibrium in skeletal muscle function, particularly in response to stressors such as physical exercise or injury. Dysregulation of this balance may contribute to chronic inflammation, muscle atrophy, and degenerative muscle disorders. Elucidating the molecular mechanisms underlying the crosstalk between calpains and NF-κB may yield significant insights for the formulation of therapeutic strategies targeting disease conditions associated with skeletal muscle. Targeting CAPN-NF-κB signaling may therefore represent a promising approach to mitigate muscle degeneration and improve muscle health under pathological conditions.</p>