<p>Synthetic cathinone-type new psychoactive substances (SCa-NPS) are the most representative subclass of synthetic stimulants, a major category of third-generation drugs monitored by the United Nations Office on Drugs and Crime. SCa-NPS rank second only to synthetic cannabinoid receptor agonists in prevalence and are characterized by rapid derivation and metabolism. This study investigated the in vitro metabolism of 3′,4′-tetramethylene-α-pyrrolidinovalerophenone (TH-PVP), for which no metabolic data currently exists, using a human liver microsomal model. Ultra-high-performance liquid chromatography-tandem quadrupole-orbitrap mass spectrometry was used to analyze TH-PVP metabolites. By comparing mass spectrometry (MS) data with literature reports and analyzing cleavage patterns, 27 metabolites across 12 categories were identified. The primary metabolic pathways—hydroxylation, β-ketoreduction, and their combinations—accounted for 91.57% of total metabolites. Building on this foundation, the metabolism of six other α-pyrrolidinopentanone-structured SCa-NPS was examined. Structural effects on α-pyrrolidinophenone-derived SCa-NPS (PP SCa-NPS) metabolism were analyzed. The β-ketoreduction metabolite content showed a linear relationship with both the Hammett substituent constants on the phenyl ring and the energy difference between the lowest unoccupied and highest occupied molecular orbitals of the parent drug. Regarding hydroxylation metabolism, TH-PVP analysis revealed preferred hydroxylation on <i>sp</i>³ carbons, particularly at the α-position of the phenyl group, followed by the pyrrolidinyl group. Moreover, MS cleavage analysis of TH-PVP metabolites indicated that hydroxylation sites could identify condensed Fukui function values, carbon radical stability, and bond dissociation energy. The findings demonstrated that metabolite relative content can be predicted through theoretical calculations combined with the structure of the parent drug.</p>