Background Several drugs have been tried to obtund the hemodynamic extubation response but all have variable side effects that may affect the quality of short-term recovery. Objective Our primary objective was to evaluate the effect of pharmacological agents, such as dexmedetomidine, local anesthetics, and so on, administered for attenuating the extubation response on the quality of extubation, as judged by the presence or absence of cough, sedation, and laryngospasm/bronchospasm in adult patients who had undergone general anesthesia. A secondary objective was to evaluate the effect of these drugs on other immediate postextubation complications such as respiratory depression, desaturation, bradycardia, hypotension, and nausea and vomiting (PONV). Methods This is a systematic review of (randomized controlled trials) RCTs with meta-analysis. The Medical Literature Analysis and Retrieval System Online (MEDLINE), Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for RCTs on the effect of pharmacological agents on both the hemodynamic extubation response as well as the quality of extubation. Results Fourteen out of 24 included studies were subjected to a meta-analysis. The risk of cough was less likely in the intervention group as compared to control groups (OR 0.26, 95% CI 0.15 to 0.46, p<0.00001, I 2 =35%). Sedation, hypotension (OR= 10.47; 95% CI: 1.86, 58.80, p=0.008, I 2 =0%), and bradycardia (OR= 6.57; 95% CI: 2.09, 20.64, p=0.001, I 2 =0%) were reported with dexmedetomidine. Only one study reported laryngospasm with dexmedetomidine and two studies with opioids.