In this study, La-doped ZnFe layered double hydroxide (La-ZnFe LDH) was immobilized on polydimethylsiloxane (PDMS) sponges and applied in the photocatalytic degradation process for the activation of peroxymonosulfate (PMS). The La-ZnFe LDH, PDMS sponge, and PDMS@La-ZnFe LDH samples were characterized by scanning electron microscopy (SEM), energy-dispersive X-ray spectrometry (EDX), X-ray diffraction (XRD), Brunauer–Emmett–Teller (BET), Fourier transform infrared (FT-IR) analyses, and contact angle goniometer. The immobilized catalyst had a porous structure with a specific surface area of 5.94 m2 g−1 and a pore volume of 1.36 cm3 g−1. The PDMS@La-ZnFe LDH has the high potential to degrade rifampicin by activating PMS with a notable synergistic factor of 3.38. The optimum operating conditions for the degradation of 15 mg L−1 of rifampicin were determined as 0.2 mmol L−1 of PMS, 100 W of light intensity, and pH of 8, conducting the degradation efficiency to 92.8% within 360 min. According to the radical quenching tests, h+, •OH, SO4•−, and O2•− exhibited an important role in the rifampicin degradation. Besides, the PDMS@La-ZnFe LDH sponge possessed excellent reusability during the PMS-activated photocatalytic process after seven consecutive runs. Furthermore, the treatment of rifampicin from real wastewater was also evaluated. GC-MS analysis was carried out to determine the generated by-products during the photocatalytic degradation process. Briefly, La-ZnFe LDH catalyst immobilized with PDMS sponges can be a promising reusable and durable photocatalyst for the degradation of refractory organic pollutants.