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Herein, we report a comparative study based on structure, thermal and solution stability, and biopotency against lipoxygenase (LOX), butyrylcholinesterase (BChE) and microbes for Pd(II) compounds of N,O,S bearing 5-(C5H4XR)-1,3,4-oxadiazole-2-thiones (L′) of type [PdL′Cl2] (P′n) and N,O bearing respective hydrazides (L) of type trans-[PdL2Cl2] (Pn) {X = C, R = 4-I, 2-Br, 4-NO2, 3-NO2, 2-Cl, 3-Cl (n = 1–6, serially); X = N (n = 7)}. Spectral techniques (IR, EI-MS, NMR) and physicochemical evaluations successfully characterized the new compounds. The L′ behaved as bidentate S-N donors bonded through exocyclic sulfur and N-3′ nitrogen, while L acted as amino N donors. UV–vis (solution speciation) and thermal degradation profiles consistently confirmed the greater stability for P′n than Pn compounds. These compounds manifested varying degree in vitro potential to inhibit LOX, BChE and several bacteria and fungi, affected mainly by Pd(II) presence, M-L binding mode, nature and position of R, or halo groups electronegativity. Molecular docking with human 5-LOX and BChE further validated the respective experimental inhibition findings and explored several putative mechanistic interactions (H-bonding, π-stacking, π-alkyl, π-S, etc.) at the enzyme active sites. Pn generally offered superior antimicrobial and anti-LOX (anti-inflammatory) potential than respective P′n compounds, with P3/P′5, P(2,3,7)/P′3, and P6 being comparable, better and equivalent to ampicillin, nystatin and baicalein, the reference antibacterial, antifungal and anti-LOX drugs, respectively. Contrarily, the anti-BChE activity of P′n was found better than Pn compounds, showing P′2/P1 as the most promising anti-Alzheimer drug candidates. This study bares important structural and mechanistic aspects in optimizing antimicrobial, anti-inflammatory and anti-Alzheimer activities, highlighting some potential future pallado-drug candidates.