Human laboratory studies are widely used to evaluate behavioural mechanisms of pharmacotherapy effects. Results from human laboratory studies examining smoking cessation pharmacotherapies have not been examined in aggregate. The current meta-analysis aimed to synthesize data from randomized, placebo-controlled human laboratory studies on the effects of non-nicotine pharmacotherapies on outcomes relevant for smoking cessation. Literature searches identified 15 human laboratory studies of varenicline (n?=?697) and 9 studies of bupropion (n?=?313) with sufficient data for inclusion. Studies involved acute or subacute pharmacotherapy treatment with administration durations ranging from a single dose to 8?weeks. Primary outcomes examined were craving, withdrawal and behavioural indices of smoking. Varenicline significantly reduced craving (Hedge's g?=??0.36[?0.54,?0.17], p?<?0.001), withdrawal (g?=??0.25[?0.41,?0.09], p?=?0.003) and behavioural indices of smoking (g?=??0.36[?0.63,?0.08], p?=?0.01) relative to placebo. In contrast, results were inconclusive regarding bupropion's effects on craving (g?=??0.13[?0.32,0.05], p?=?0.15), withdrawal (g?=??0.15[?0.44,0.14], p?=?0.31) and behavioural indices of smoking (g?=??0.05[?0.35,0.24], p?=?0.73) relative to placebo. Findings provide meta-analytic support that short-term varenicline treatment decreases craving, withdrawal symptoms and smoking behaviour under controlled laboratory conditions. However, findings also suggest the ability of human laboratory paradigms to detect pharmacotherapy effects may differ by treatment type. Pharmacotherapy discovery and evaluation efforts utilizing human laboratory methods should aim to align study designs and laboratory procedures with presumed therapeutic mechanisms when possible.