Nociplastic pain is the fourth category of pain defined in recent years. It is a pain arising from altered nociception, despite the lack of clear evidence of actual or threatened tissue damage that causes activation of peripheral nociceptors nor evidence for disease or lesion of the somatosensory system causing the pain. This type of pain is usually multifocal, more diffuse or intense than expected and it is usually associated with other central nervous system-derived symptoms, such as fatigue, sleep, memory, and mood problems. It can occur in isolation or as part of a mixed-pain state in combination with ongoing nociceptive or neuropathic pain. It is associated with increased social and sanitary costs due to the difficulty of adequately treating it. Its pathogenesis is still poorly understood, even if a mounting body of evidence suggests a pivotal role in inflammation and immunity, which may be triggered by an infection and/or a trauma. This narrative review aims to summarise the current knowledge about the interplay of the immune system and nociplastic pathways activation and amplification. The challenge for the future will be to identify the exact role of inflammation and immunity, the cause of this activation, and its link to other pathogenetic factors of nociplastic pain, such as diet or microbiota alteration, social and phycological factors, together with a genetic and epigenetic predisposition.