Pain is an unpleasant sensation that has complex and varying causative etiology. Modern drug discovery focuses on identifying potential molecules that target multiple pathways with a safer profile compared to those with a single target. The current treatment of pain and inflammation with the available therapeutics has a number of major side effects. Pain is one of the major clinical problems that need functional therapeutics which act on multiple targets and with low toxicity. Curcumin, a naturally occurring polyphenolic compound from Curcuma longa, has been used for years in Ayurvedic, Chinese, and in many other systems of traditional medicine. Pre-clinical data published thus far demonstrated that curcumin possesses multi-target biological functions, suggesting its potential use to cure different diseases. However, there is no or very brief systematic review of its potential use in pain and inflammation with underlying mechanisms for such activities. Accordingly, the aim of the current review was to update the pre-clinical data of curcumin and its multiple targeting pathways for analgesic and anti-inflammatory effects, and to further propose a molecular mechanism(s). A literature study was conducted using different known databases, including Pubmed, SciFinder, Google Scholar, and Science Direct. Available pre-clinical data suggest the ameliorating effect of curcumin in pain and inflammation is rendered through the modulation of pain pathways, including inhibition of a number of pro-inflammatory mediators, inhibition of oxidative stress and cyclooxygenase-2 (COX-2), down-regulation of Ca2+/calmodulin-depend protein kinase II (CaMKIIα) and calcium channels like transient receptor potential (TRP), modulation of metabotropic glutamate receptor-2 (mGlu2), modulation of monoamine system, inhibition of JAK2/STAT3 signaling pathway, remodeling of extracellular matrix proteins, inhibition of apoptosis, inhibition of JNK/MAPK and ERK/CREB signaling pathway, and activation of the opioid system. Taken all together, it is evident that curcumin is one of the promising, safe, and natural polyphenolic molecules that target multiple molecular pathways in pain and can be beneficial in the treatment and management of pain and inflammation.