Progesterone receptor (PR) signaling plays a pivotal role in uterine fibroids (UFs) development and progression. Selective progesterone receptor modulators (SPRMs) and plant-derived PR modulators have emerged as promising therapeutic strategies. This review synthesizes current evidence on novel synthetic SPRMs and natural compounds with PR-modulating activity. Following the PRISMA guidelines, literature searches in PubMed, Scopus, and Google Scholar identified 22 studies that met the eligibility criteria. Synthetic SPRMs act mainly through PR antagonism, with differences in receptor selectivity and endometrial safety between full and partial antagonists. Plant-derived modulators have broader biological effects, including influencing apoptosis, extracellular matrix remodeling, oxidative stress, immune regulation, and autophagy. Both synthetic and plant-derived PR modulators represent potential therapeutic options for UFs. Fully antagonistic SPRMs may provide potency and receptor selectivity, whereas partial antagonists may offer superior endometrial tolerability for long-term use. All novel SPRMs are non-steroidal and lack the dimethylaminophenyl moiety, which may enhance their safety and tolerability. Plant-derived agents could serve as adjunctive or alternative therapies through their multi-pathway actions. Collectively, these findings support the integration of precision medicine through SPRMs with the broader therapeutic benefits offered by plant-derived compounds. © 2026 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn.