Large numbers of local and systemic therapies are available for acne treatment. Common oral or topical retinoids, antibiotics, or keratolytics are used but sometimes are inconvenient, and side effects caused by these conventional therapies prompted a search for effective and safe treatments. This study aimed to evaluate the efficacy of intralesional platelet-rich plasma injection versus 1064 nm long-pulsed Nd:YAG laser in the treatment of moderate inflammatory acne vulgaris in both adolescents and post-adolescent patients. This split-face comparative study was carried out on thirty patients who suffered from moderate inflammatory and non-inflammatory acne vulgaris. The patients were classified into two groups: group I: adolescent (≤ 25 years) and group II: post-adolescent (< 25 years). Each group received four sessions of intralesional PRP injection on one side of the face and a long-pulsed Nd:YAG (1064 nm) laser on the other side with 2 weeks interval. Evaluation was done by blinded dermatologists using photographs and lesions counting and by patient satisfaction. Side effects were also noted. Both groups (adolescents and post-adolescent) showed a high statistically significant improvement of inflammatory as well as non-inflammatory lesions either in PRP or Nd:YAG laser-treated side with no significant difference between the two sides. The intralesional PRP injection and 1064 nm long-pulsed Nd:YAG laser are safe and effective methods for controlling inflammatory as well as non-inflammatory acne vulgaris in both adolescents and post-adolescent patients.