Class-3 semaphorins (SEMA3s), initially characterized as axon guidance cues, have been recognized as key regulators for immune responses, angiogenesis, tumorigenesis and drug responses. The functions of SEMA3s are attributed to the activation of downstream signaling cascades mainly mediated by cell surface receptors neuropilins (NRPs) and plexins (PLXNs), yet their roles in human cancers are not completely understood. Here, we provided a detailed pan-cancer analysis of NRPs and PLXNs in their expression, and association with key signal transducers, patient survival, tumor microenvironment (TME), and drug responses. The expression of NRPs and PLXNs were dysregulated in many cancer types, and the majority of them were further dysregulated in metastatic tumors, indicating a role in metastatic progression. Importantly, the expression of these genes was frequently associated with key transducers, patient survival, TME, and drug responses; however, the direction of the association varied for the particular gene queried and the specific cancer type/subtype tested. Specifically, NRP1, NRP2, PLXNA1, PLXNA3, PLXNB3, PLXNC1, and PLXND1 were primarily associated with aggressive phenotypes, whereas the rest were more associated with favorable prognosis. These data highlighted the need to study each as a separate entity in a cancer type- and subtype-dependent manner.