Inflammation is a central process in homeostasis, and dysfunctional inflammatory responses have important implications in disease, for instance in severe COVID-19 pathogenesis and cancer. Inflammation is a metabolically demanding process, and targeting immune cell metabolism may open novel avenues for treatment of aberrant inflammatory diseases and malignancies. Production of high quantities of nitric oxide (NO) by the enzyme inducible NO synthase (iNOS) is found in chronic inflammation and cancer and is implicated in pathology. Here, we demonstrate that iNOS expression and activity are also enhanced in colon and prostate cancer and in severe COVID-19 disease. iNOS is expressed, although at low percentages, by human macrophages from tumours and from bronchoalveolar lavage fluid of severe COVID-19 patients. While macrophages do not comprise the main source of iNOS in tissue, we demonstrate that NO produced by neighbouring cells is sufficient to induce nitrotyrosine (NT) formation in macrophages, thus mediating its actions on these cells. Moreover, we show that both endogenous and exogenous NO promote alterations in macrophage effector function, favouring a pro-inflammatory phenotype and contributing to enhanced and sustained pro-inflammatory cytokine secretion. NO also reduces antigen presenting function of macrophages and impairs several M2 functions. NO mediates its effects by mitochondria-dependent mechanisms, through inhibition of respiration, and mitochondria-independent actions by HIF-1-alpha stabilisation. We also highlight a relationship between iNOS, COX-2 and HIF-1-alpha in macrophages, which may be relevant in the context of inflammation and cancer. Our results suggest that NO favours exaggerated pro-inflammatory responses, subverts adaptive immunity responses and impairs healing, which may contribute to inflammation that favours tumour development and growth and that is characteristic of severe COVID-19. Targeting inflammation and metabolism through NO signalling may be beneficial in such diseases. Systemic NO generation, evidenced by levels of protein-bound NT, may also predict COVID-19 severity and outcome, and further investigations are needed to evaluate its prognostic value in cancer.