Background: Poor adherence to drug is an important cause of not achieving treatment targets among female patients with lupus nephritis flares. Aim: to evaluate the effect of targeted nursing instructions protocol on knowledge and therapeutic adherence among female patients with lupus nephritis flares. Research design: A quasi experimental (pre-posttest) research design was utilized. Sample: A purposeful sample of (200) female patients with lupus nephritis flares with an age range from 20 to 65 years old . Setting: The study was conducted in the Internal Medical & Rheumatology Department at the Main Assiut University Hospital and its affiliated clinics. Tools: Tools (I): Patient Structured Interview Questionnaire. Tool (II): General Level Knowledge Structured Questionnaire Tool (III): Medication adherence scale. Results: There were a statistically significant difference was found between the pre and post implementation of the protocol regarding the total scores of knowledge level & medication adherence during (3 &6 months after implementing the target nursing instructions protocol with P = (0.001). Conclusion: Targeted nursing educational protocol was effective in improving knowledge level and medication adherence for female patients with lupus nephritis flares. Recommendation: Targeted nursing program is effective on early prediction of complications among patients with lupus nephritis flares.