Fluvoxamine (FXM) is a well-known selective serotonin reuptake inhibitor (SSRI) for treating depression and has recently been repurposed for efficacious treatment of coronavirus disease 2019. Although cyclodextrin (CD) encapsulation effectively improves the physicochemical properties of structurally diverse SSRIs, the molecular understanding of their associations is deficient. This comprehensive study used single-crystal X-ray diffraction integrated with density functional theory (DFT) calculation to provide deep insights into the conformationally flexible FXM and its inclusion complexation with β-CD. X-ray analysis revealed the first crystallographic evidence of the uncomplexed 3FXM-H⁺·3maleate^- (1). Three FXM-H⁺ ions are counter-balanced by three planar maleate^- ions to form a thin layer stabilized by infinite fused H-bond rings R₄ ⁴(12) and R₆ ⁴(16) and the interplay of π⋯π, CF⋯π and F⋯F interactions. For 2β-CD·2FXM-H⁺·maleate^2-·23·2H₂O (2), the tail-to-tail β-CD dimer encapsulates two FXM-H⁺ 4-(trifluoromethyl)phenyl moieties, which are charge-balanced by the rare non-planar maleate^2- and stabilized by N/OH⋯O H-bonds and F⋯F interactions. This is a host-guest recognition pattern uniquely observed for all β-CD complexes with halogen (X)-bearing SSRIs, indicating the essence of X⋯X interactions and the shielding of X-containing moieties in the wall of the β-CD dimer. DFT calculations unveiled that the monomeric and dimeric β-CD-FXM complexes and FXM isomers are energetically stable, which alleviates the numbness and bitterness of the orally administered drug as previously patented. Additionally, an insightful conformational analysis of FXM emphasizes the importance of drug structural adaptation in pharmacological functions.