Introduction: To compare the effect of three different anti-inflammatory regimens consisting of preservative-free dexamethasone (DEX), diclofenac (DICLO) eye drops, and their combination (DEX + DICLO) following trabeculectomy on early postoperative inflammation. Methods: A prospective randomized controlled trial. Sixty-nine patients undergoing trabeculectomy were randomized to receive either postoperative treatment with topical DEX (n = 23), topical DICLO (n = 23), or a combination of topical DEX and topical DICLO (n = 23) after trabeculectomy. The primary outcome was the anterior chamber flare measurement in the first 3 months postoperatively. Secondary outcomes included intraocular pressure, central corneal thickness, conjunctival injection, and number of cells in the anterior chamber from baseline to 3 months postoperatively. Results: Anterior chamber flare reached a maximum 1 day after trabeculectomy with an increase of 55% (95% CI 37–73%) for DEX, 64% (95% CI 47–82%) for DICLO, and 57% (95% CI 39–75%) for DEX + DICLO and returned to near pre-operative values 6 weeks after surgery. There were no significant differences in anterior chamber flare [effect size for DICLO: 0.16 (95% CI − 4.3 to 4.6), effect size for DEX + DICLO: 0.09 (95% CI − 4.1 to 4.3)], intraocular pressure, central corneal thickness, conjunctival injection, or number of cells in the anterior chamber between DEX, DICLO, or DEX + DICLO groups. Conclusion: We found that topical diclofenac was not statistically different from topical dexamethasone in controlling early postoperative inflammation after trabeculectomy, while combining diclofenac and dexamethasone offered no added anti-inflammatory control compared to dexamethasone alone. Trial Registration: www.clinicaltrials.gov (NCT04054830).