Benign prostatic hyperplasia (BPH) is a nonmalignant growth of the prostate tissue and causes urinary tract symptoms. To provide effective treatment, tamsulosin (TM), saw palmetto oil (SP), and pumpkin seed oil (PSO) were combined and fabricated a nanostructured lipid carrier (NLC) as TM-S/P-NLC using experimental design. The purpose was to enhance the permeation and therapeutic activity of TM; combining TM with SP and PSO in an NLC generates a synergistic activity. An optimized TM-S/P-NLC was obtained after statistical analysis, and it had a particle size, percentage of entrapment efficiency, and steady-state flux of 102 nm, 65%, and 4.5 μg/cm 2 .min, respectively. Additionally, the optimized TM-S/P-NLC had spherical particles with a more or less uniform size and a stability score of 95%, indicating a high level of stability. The in vitro release studies exhibited the optimized TM-S/P-NLC had the maximum release profile for TM (81 ± 4%) as compared to the TM-NLCs prepared without the addition of S/P oil (59 ± 3%) or the TM aqueous suspension (30 ± 5%). The plasma TM concentration–time profile for the TM-S/P-NLC and the marketed TM tablets indicated that when TM was supplied in a TM-S/P-NLC, the pharmacokinetic profile of the drug was improved. Simultaneously, in vivo therapeutic efficacy studies also showed favorable results for the TM-S/P-NLC in terms of the prostate weight and prostate index following treatment of BPH. Based on the findings of present study, we suggest that in the future, the TM-S/P-NLC could be a novel drug delivery system for treating BPH.