The hyperinflammatory response in COVID-19 is a major factor contributing to morbidity. Pentoxifylline, a methylxanthine derivative, has immunomodulatory properties, but its effects on inflammatory markers in COVID-19 remain unclear. This meta-analysis aims to evaluate the efficacy of pentoxifylline supplementation on CRP and interleukin-6 (IL-6) levels in these patients. A systematic search was conducted across multiple databases for randomized controlled trials (RCTs) published up to September 2025. Four RCTs, including 178 cases and 321 controls for CRP, and two RCTs, including 70 cases and 70 controls for IL-6, were included. Two reviewers independently performed data extraction and assessed the risk of bias using the Cochrane tool. Pooled standardized mean differences (SMDs) were calculated using a random-effects model. Heterogeneity was analyzed through meta-regression, and the conclusiveness of the evidence was evaluated using Trial Sequential Analysis (TSA). Pentoxifylline did not significantly reduce C-reactive protein (CRP) levels compared to the control group (SMD = −0.89; 95% CI: −1.85 to 0.07; p = 0.07). However, substantial heterogeneity was noted across the studies (I² = 95.3%). Similarly, a nonsignificant trend toward reduction was observed for IL-6 (SMD = −0.22; 95% CI: −0.96 to 0.52; p = 0.55), accompanied by significant heterogeneity (I² = 79.1%). Given the limited number of studies included, the results are inherently fragile, and one additional trial could substantially shift the pooled estimate. Meta-regression analysis indicated that patient age and publication year did not account for the heterogeneity, although there was a nonsignificant trend suggesting that a longer treatment duration might be associated with greater CRP reduction. TSA for CRP showed that cumulative evidence suggested futility and a lack of meaningful effect, confirming a significant lack of effect. The included studies generally had a low risk of attrition and reporting bias. Current evidence does not support the use of pentoxifylline for significantly reducing CRP or IL-6 levels in COVID-19 patients. The findings regarding CRP are considered conclusive, but the limited number of studies suggests that further trials on this outcome may alter this conclusion.