Microalgal-based remediation is an ecofriendly and cost-effective system for wastewater treatment. This study evaluated the capacity of microalgae in the remediation of wastewater from cleaning process of smoked cigarette butts (CB). At laboratory scale, six strains (one from the family Scenedesmaceae, two Chlamydomonas debaryana and three Chlorella sorokiniana) were exposed to different CB wastewater dilutions to identify toxicity levels reflected in the alteration of microalgal physiological status and to determine the optimal conditions for an effective removal of contaminants. CB wastewater could impact on microalgal chlorophyll and carotenoid production in a concentration-dependent manner. Moreover, the resistance and remediation capacity did not only depend on the microalgal strain, but also on the chemical characteristics of the organic pollutants. In detail, nicotine was the most resistant pollutant to removal by the microalgae tested and its low removal correlated with the inhibition of photosynthetic pigments affecting microalgal growth. Concerning the optimal conditions for an effective bioremediation, this study demonstrated that the Chlamydomonas strain named F2 showed the best removal capacity to organic pollutants at 5% CB wastewater (corresponding to 25 butts L−1 or 5 g CB L−1) maintaining its growth and photosynthetic pigments at control levels.