The ecological risks brought by heavy metals and 4-monobromodiphenyl ether (BDE-3) copollutants are among the most common environmental contaminants. Heavy metals and other substrates are actively transported across cellular membranes by an ATP-binding cassette (ABC) transporter. Previous studies have suggested that phyllospheric yeast (Wickerhamomyces anomalus) can survive in BDE-3 and heavy metal environments. However, the underlying molecular mechanisms of BDE-3 and heavy metal tolerance are not clear. To assess the impact of the yeast transporter pdr15 gene on plant tolerance, tissue heavy metal levels, and BDE-3 levels, we heterologously expressed the gene in tobacco. Accumulating evidence has suggested that transgenic tobacco contributes to the reduction of plant damage by resulting in heavy metals and BDE-3 in specific subcellular organelles. Dimethyl ether and phthalic acid metabolism were the two main metabolic pathways for the toxicity-reducing effect. Our findings broaden the understanding of ABC transporter function and their regulatory metabolic pathways in heavy metal and BDE-3 co-contaminated resistance.