The essential oil industry of aromatic herbs and spices is currently producing a significant amount of by-products, such as the spent plant materials remaining after steam or hydrodistillation, that are simply discarded. The aim of this study was to comparatively investigate the phytochemical composition, antioxidant and multi-enzymatic inhibitory potential of the essential oils and spent plant material extractives obtained from cinnamon, cumin, clove, laurel, and black pepper. The essential oils were characterized by the presence of several phytochemical markers (cinnamaldehyde, cuminaldehyde, eugenol, eucalyptol, α-terpinene, limonene, β-caryophyllene or β-pinene). On the other hand, the LC-HRMS/MS profiling of the spent material extracts allowed the annotation of species specific and non-specific metabolites, such as organic acids, phenolic acids, flavonoids, proanthocyanidins, hydrolysable tannins, fatty acids, or piperamides. All samples exhibited very strong antioxidant effects, with the clove essential oil displaying the strongest radical scavenging (525.78 and 936.44 mg TE/g in DPPH and ABTS assays), reducing (2848.28 and 1927.98 mg TE/g in CUPRAC and FRAP), and total antioxidant capacity (68.19 mmol TE/g). With respect to the anti-acetylcholinesterase (0.73–2.95 mg GALAE/g), anti-butyrylcholinesterase (0–3.41 mg GALAE/g), anti-tyrosinase (0–76.86 mg KAE/g), anti-amylase and anti-glucosidase (both 0–1.00 mmol ACAE/g) assays, the spice samples showed a modest activity. Overall, our study reports that, not only the volatile fractions of common spices, but also their spent plant materials remaining after hydrodistillation can be regarded as rich sources of bioactive molecules with antioxidant and multi-enzymatic inhibitory effects.