We investigated and monitored in situ the wetting and dissolution properties of polymeric nanofibers and determined the solid-state of a drug during dissolution. Piroxicam (PRX) was used as a low-dose and poorly-soluble model drug, and hydroxypropyl methylcellulose (HPMC) and polydextrose (PD) were used as carrier polymers for electrospinning (ES). The initial-stage dissolution of the nanofibers was monitored in situ with three-dimensional white light microscopic interferometry (SWLI) and high-resolution optical microscopy. The physical solid-state characterization of nanofibers was performed with Raman spectroscopy, X-ray powder diffraction (XRPD), and scanning electron microscopy (SEM). We showed that PRX recrystallizes in a microcrystalline form immediately after wetting of nanofibers, which could lead to enhanced dissolution of drug. Initiation of crystal formation was detected by SWLI, indicating: (1) that PRX was partially released from the nanofibers, and (2) that the solid-state form of PRX changed from amorphous to crystalline. The amount, shape, and size of the PRX crystals depended on the carrier polymer used in the nanofibers and dissolution media (pH). In conclusion, the present nanofibers loaded with PRX exhibit a quasi-dynamic dissolution via recrystallization. SWLI enables a rapid, non-contacting, and non-destructive method for in situ monitoring the early-stage dissolution of nanofibers and regional mapping of crystalline changes (re-crystallization) during wetting. Such analysis is crucial because the wetting and dissolution of nanofibers can greatly influence the performance of nanofibrous drug delivery systems in pharmaceutical and biomedical applications.