Mycobacterium avium (Mav) complex is the leading cause of pulmonary diseases associated with non-tuberculous mycobacterial (NTM) infections worldwide. The inherent and increasing acquired antibiotic resistance of Mav hampers the treatment of Mav infections and emphasizes the urgent need for alternative treatment strategies. A promising approach is host-directed therapy (HDT), which aims to boost the host’s immune defenses to combat infections. In this study, we show that phenothiazines, particularly trifluoperazine (TFP) and chlorproethazine (CPE), restricted Mav survival in primary human macrophages. Notably, TFP and CPE did not directly inhibit mycobacterial growth at used concentrations, confirming these drugs function through host-dependent mechanisms. TFP and CPE induced a mild, albeit not statistically significant, increase in autophagic flux along with the nuclear intensity of transcription factor EB (TFEB), the master transcriptional regulator of autophagy. Inhibition of autophagic flux with bafilomycin, however, did not impair the improved host infection control by TFP and CPE, suggesting that the host (auto)phagolysosomal pathway is not causally involved in the mechanism of action of TFP and CPE. Additionally, TFP and CPE increased the production of both cellular and mitochondrial reactive oxygen species (ROS). Scavenging mitochondrial ROS did not impact, whereas inhibition of NADPH oxidase (NOX)-mediated ROS production partially impaired the HDT activity of TFP and CPE, indicating that oxidative burst may play a limited role in the improved host control of Mav infection by these drugs. Overall, our study demonstrates that phenothiazines are promising HDT candidates that enhance the antimicrobial response of macrophages against Mav, through mechanism(s) that were partially elucidated.