Background Pleural disease prevalence continues to rise, so pleural biopsy is commonly required. The ultrasound’s role in directing pleural biopsy ensures more safety. Pain management is crucial for both procedure success and patient satisfaction. This is a unique randomized controlled trial for pain management during pleural biopsy. Patients and methods Sixty-four patients were enrolled and randomized into two groups using the simple randomization method (1: 1). Group I received a placebo. Group II received a single dose of 75 mg intravenous diclofenac sodium before the procedure. Five milliliters of subcutaneous lidocaine was administered to both groups 2 min before the procedure. The pain was evaluated using the visual analogue scale (VAS), modified adult nonverbal pain scale (ANVPS), and Likert scale. Results Group I had significantly longer procedure duration and pain. Regarding VAS 30, 60 min, and 24 h after the procedure (significantly higher among group I) (P value <0.001) and ANVPS 30–60 min after the procedure (significantly higher among group I) (P value 0.002 and <0.001, respectively). Regarding satisfaction scores at 30 and 60 min (significantly lower in group I) (P value <0.001). Regarding late complications (swelling, hematoma, and pain), all prevailed higher among group I (P value <0.001). Conclusion Combined local anesthesia and single-dose analgesia could be better than local anesthesia alone in pain control during and after transthoracic ultrasound-guided pleural biopsy, according to VAS and ANVPS. Pain control may result in shorter procedure duration, higher patient satisfaction, and a lower rate of procedure-related late complications.