The essential oil ofMyristica fragransHutt. (nutmeg) is an important commodity used as a flavoring agent in the food, pharmaceutical, and cosmetic fields. Hydrodistillation is chiefly employed at the industrial scale for nutmeg essential oil isolation, but such a technique generates large quantities of post-distillation by-products (e.g., spent plant material and residual distillation water). Therefore, our work aimed to propose a novel strategy for the valorization of nutmeg wastes, with beneficial economic and ecological advantages. Thus, the current study assessed the phytochemical (GC-MS, LC-HRMS/MS) and biological (antioxidant, enzyme inhibitory, antimicrobial) profile of nutmeg crude materials (essential oil and total extract) and post-distillation by-products (residual water and spent material extract). Identified in these were 43 volatile compounds, with sabinene (21.71%),α-pinene (15.81%), myristicin (13.39%), andβ-pinene (12.70%) as the main constituents. LC-HRMS/MS analysis of the nutmeg extracts noted fifteen metabolites (e.g., organic acids, flavonoids, phenolic acids, lignans, and diarylnonanoids). Among the investigated nutmeg samples, the spent material extract was highlighted as an important source of bioactive compounds, with a total phenolic and flavonoid content of 63.31 ± 0.72 mg GAE/g and 8.31 ± 0.06 mg RE/g, respectively. Moreover, it showed prominent radical-scavenging and metal-reducing properties and significantly inhibited butyrylcholinesterase (4.78 ± 0.03 mg GALAE/g). Further, the spent material extract displayed strong antimicrobial effects againstStreptococcus pneumoniae,Micrococcus luteus, andBacillus cereus(minimum inhibitory concentrations of 62.5 mg/L). Overall, our study brings evidence on the health-promoting (antioxidant, anti-enzymatic, antimicrobial) potential of nutmeg post-distillation by-products with future reference to their valorization in the pharmaceutical, cosmeceutical, and food industries.