Both pain and itch are important protective sensations of the human body, which could induce reflective behaviors such as withdraw and scratch when facing danger. Pain and itch have some similarities in the process of sensory information transmission and modulation, but whether the two sensations share the same neural pathway is still controversial. Most of the existing research focuses on a single level (e.g., neurons, fibers, or brain regions) to explore the relationship between two sensations. Here, we discussed the similarities and differences of neural mechanisms between pain and itch perceptions from bottom-up and top-down pathways of the peripheral and central nervous system based on recent neuroimaging and electrophysiological studies. First, we reviewed the neural coding mechanisms of pain and itch on the peripheral nervous system and central nervous system. Existing research based on the peripheral nervous system shows that the itch reception and nociception induced by different stimuli, such as heat pain, mechanically pain, histamine dependent and independent itch, selectively transmit through different primary afferent nerves, including Aδ and C fibers. Furthermore, we summarized the roles of the spinothalamic tract and the spinoparabrachial pathway in the sensory information transmission of pain and itch sensations separately at the spinal cord level. Then we compared the specific brain regions related to these two sensations, including the insula, amygdala, cingulate cortex, primary and secondary sensory cortex, which composed a "matrix" responsible for producing the perception of itch and pain but with different features. Second, we introduced the descending pain modulation system with critical regions of the periaqueductal gray (PAG) and the rostral ventromedial medulla (RVM), and we compared the different modulation mechanisms of pain and itch perceptions in the central nervous system. Meanwhile, we explained the pain and itch analgesic mechanism in the view of bidirectional modulation involved the reward system, which usually considered merely the opposite of aversive somatosensory system. The existing research conclusion showed that the neural mechanisms of pain and itch are not purely independent, overlapping, or antagonistic, but have very complex interactions. To reveal the underlying mechanisms of complex interactions, more precise neurological techniques (e.g., high-resolution head-neck combined imaging) are needed for future studies. To distinguish the mechanisms of pain and itch sensations are very important to the targeted clinical treatment. Our review summarized their similarities and differences, which could provide some new insights to explore the useful treatment directions.