Chronic pruritus has been associated with the neurokinin 1 receptor (NK1R) and its agonist substance P (SP). With the recent disclosure of the receptor’s crystallographic structure, the design of new NK1R antagonists was facilitated. In the marine environment, several SP antagonists were isolated inspiring the synthesis of novel compounds. Since pruritus and inflammation often go together, developing compounds with antipruritic and anti-inflammatory activities is a promising strategy. Therefore, we aim for the structure-based drug design of new SP antagonists based on marine natural products (MNP) to obtain innovative compounds for topical treatment of pruritus-associated inflammatory skin diseases and to evaluate their activity in silico and in vitro. In silico, eighteen marine-inspired compounds were found to bind to NK1R with better or equal docking scores than the natural MNP and demonstrated positive pharmacokinetic properties for skin permeation. In vitro, no relevant cytotoxicity and a 50% reduction in the release of the pro-inflammatory mediator nitric oxide (NO) was detected. The significant decrease in inducible nitric oxide synthase (iNOS) protein levels and NO release, together with the absence of NO-scavenging potential, suggests the blockage of pro-inflammatory signaling pathways upstream of iNOS synthesis. A structure-activity relationship was established, and two new compounds have already been synthesized by two different pathways and structurally characterized. Marine-inspired products are promising sources of anti-inflammatory compounds and NK1R antagonists for the treatment of skin conditions characterized by pruritus and inflammation.