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Therefore, the search for more effective and safer anticancer drugs remains an urgent priority. This study aimed to identify plant extracts from the Andalusian flora (Southern Spain) with selective anticancer potential. Methodology: A total of 67 extracts from 59 plant species were screened for selective cytotoxicity using A549 lung adenocarcinoma and HaCaT non-malignant cells. The most promising candidates, extracts from Thymelaea lanuginosa and Daphne oleoides, were further evaluated through fluorescence-based co-cultures, cell cycle analysis, and redox-mechanism assay. These extracts were also tested against a panel of cancer cells derived from different tissues (MDA-MB-231, T24, KATO-III, SK-OV-3, and MeWo). Results: Several extracts exhibited selective activity against A549 cancer cells, including extracts from Chamaeiris foetidissima (L.) Medik. (=Iris foetidissima L.), Daphne oleoides Schreb, Iberodes linifolia (L.) M. Serrano, R. Carbajal &amp; S. Ortiz, Reseda media Lag., Saxifraga hirsuta L., Seseli montanum subsp. granatense (Willk.) C. Pardo, Thymelaea lanuginosa (Lam.), and Tordylium officinale L. The extracts from D. oleoides and T. lanuginosa were over 1000 times more active against lung cancer cells than non-malignant cells. These extracts induced a specific G1-phase arrest in A549 cells. Both extracts showed also selective activity against triple-negative breast cancer cells (MDA-MB-231) and bladder cancer cells (T24). Conclusions: These findings highlight Daphne and Thymelaea species as valuable sources for discovering novel selective anticancer agents. Future research should focus on bio-guided fractionation and in vivo validation to fully delineate their therapeutic potential.<\/jats:p>","DOI":"10.3390\/ph19040616","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T08:14:17Z","timestamp":1776154457000},"page":"616","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Screening for Selective Anticancer Activity of Extracts from 59 Plant Species Collected in Southern Spain (Andalusia)"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1129-2080","authenticated-orcid":false,"given":"V\u00edctor","family":"Jim\u00e9nez-Gonz\u00e1lez","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2928-7423","authenticated-orcid":false,"given":"Guillermo","family":"Ben\u00edtez","sequence":"additional","affiliation":[{"name":"Department of Botany, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio Enrique","family":"Pastor","sequence":"additional","affiliation":[{"name":"Department of Vegetal Biology and Ecology, Faculty of Biology, University of Seville, 41012 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2794-1647","authenticated-orcid":false,"given":"Miguel","family":"L\u00f3pez-L\u00e1zaro","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6845-797X","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"Calder\u00f3n-Monta\u00f1o","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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