Background and Objectives: To elucidate the material basis and molecular mechanisms of the Rehmanniae Radix–Sophorae Flos (RR-SF) herb pair for psoriasis treatment, and to verify causal effects of core targets from a genetic perspective, constructing an integrated “component–target–pathway–causality” evidence chain. Materials and Methods:A four-level strategy was employed: (1) UPLC-Q-TOF/MS identified chemical constituents of the RR-SF co-decoction; (2) network pharmacology screened active compounds (OB ≥ 30%, DL ≥ 0.10), predicted targets, constructed drug–compound–target–pathway and PPI networks, and performed GO/KEGG enrichment; (3) drug-target Mendelian randomization (MR) used eQTLs of 7 core targets as exposure and psoriasis GWAS as outcome, with IVW as primary method and MR-Egger, Cochran’s Q, leave-one-out, and Steiger tests for sensitivity analysis; (4) AutoDock Vina molecular docking verified binding between active compounds and core targets. Results: 109 constituents were identified, dominated by flavonoids (32), iridoids (26), and phenylethanoid glycosides (12). Network pharmacology yielded 14 active compounds and 159 shared targets, with SRC, MAPK3, RXRA, HSP90AA1, CTNNB1, AKT1, and MAPK1 as core hubs. Key pathways included IL-17, MAPK, Th17 differentiation, VEGF, PI3K-Akt, and NF-κB. MR confirmed causal associations: MAPK1 (OR = 2.58, 95% CI 1.49–4.46, P = 7.5 × 10⁻⁴, risk), HSP90AA1 (OR = 0.42, 95% CI 0.24–0.74, P = 2.6 × 10⁻³, protective), and SRC (OR = 2.00, 95% CI 1.04–3.87, P = 0.039). MAPK1 and HSP90AA1 remained significant after Bonferroni correction. Molecular docking identified quercetin–HSP90AA1 (−9.3 kcal/mol) and aeginetic acid–RXRA (−9.1 kcal/mol) as strongest interactions. Conclusions: RR-SF exerts anti-psoriatic effects via a multi-component–multi-target–multi-pathway mode. MR validated causality of core targets, and molecular docking identified quercetin–HSP90AA1 and aeginetic acid–RXRA as key intervention strategies, providing multi-dimensional evidence for precision psoriasis treatment.