Background <p>Despite the minimally invasive nature of laparoscopic surgery, postoperative pain remains a highly prevalent clinical issue. Whether dexamethasone combined with different local anesthetic adjuvants can optimize the analgesic efficacy of ultrasound-guided transversus abdominis plane block (TAPB) remains inconclusive. This study aimed to investigate the analgesic effect of dexamethasone combined with different adjuvants for TAPB in laparoscopic surgery.</p> Methods <p>This randomized controlled trial enrolled 200 eligible patients undergoing laparoscopic surgery with TAPB, randomly assigned to 4 groups (<i>n</i> = 50 each): dexamethasone alone (Group D), dexamethasone plus dexmedetomidine (Group DD), dexamethasone plus magnesium sulfate (Group DE), and dexamethasone plus both adjuvants (Group DM). The primary outcome was time to first patient-controlled intravenous analgesia (PCIA) request within 72&#xa0;h postoperatively.</p> Results <p>Time to first PCIA request was significantly prolonged in Group DD (724.0,515.0) and Group DM (843.0,587.5) versus Group D (220.0,155.0), with Bonferroni <i>p</i> value &lt; 0.01. With significantly lower 72-h PCIA use incidence (<i>P</i> &lt; 0.05). No statistically significant differences were observed between Group DE and Group D.</p> Conclusions <p>Dexamethasone combined with dexmedetomidine for TAPB provides superior postoperative analgesia and reduces opioid consumption in laparoscopic surgery, while 200&#xa0;mg magnesium sulfate offers no additional analgesic benefit.</p> <p><i>Trial registration</i> The study has been registered with the China Clinical Trial Registration Center (ID: ChiCTR2300071199), on May 08, 2023.</p>