Introduction: Alzheimer's disease (AD) is characterized by the accumulation of the amyloid-β (Aβ) peptide in its oligomeric and fibrillar conformations, which disrupts several neuronal functions, including the autophagy–lysosomal pathway, essential for eliminating misfolded, aggregated, or mutated proteins and maintaining proteostasis. Cathepsin D, the most abundant lysosomal peptidase, is dysfunctional in AD, and in this study, we evaluated the effects of molecules from marine invertebrates on restoring its activity. Methods: Differentiated SH-SY5Y cells were pre-treated with oAβ42 (5 μM) for 48 hours, followed by treatment with venom from six Brazilian marine invertebrate species (1 mg/mL) for 24 hours. After the treatment, cell lysates were obtained, and the cathepsin D activity was measured using a specific substrate (GKPILFFRLK(Dnp)-D-R-NH2-MCA) and the fluorescence intensity monitored every five minutes (λex =: 405 nm, λem: 495 nm). The secretions were fractionated through solid-phase extraction in a C18 cartridge, eluted using acetonitrile/0.1% trifluoroacetic acid, and tested again. Results: oAβ42 decreased the velocity of cathepsin D's enzymatic reactions by 40% compared to those in the control (cells without treatment). Venom from the corals Renilla reniformis and Tubastraea tagusensis the sea anemone Anthopleura cascaia; and the sea urchin Echinometra lucunter restored the cathepsin D activity, bringing it back to the control levels or even exceeding them. The venom from A. cascaia, which exhibited the most intense activity, was fractionated further and analyzed, and an active fraction rich in peptides and small molecules was identified. Conclusion: Marine-derived molecules could restore the activity of the main lysosomal enzyme, cathepsin D, important for the elimination of the amyloid peptide and reductions in neuron death, which could contribute significantly to new therapies for the treatment of AD.