Brain-derived neurotrophic factor (BDNF) binds to the high-affinity tropomyosin-related kinase B (TrkB) receptor to mediate neuronal survival and maturation and provide neuroprotection. Activating the BDNF-TrkB pathway has significant potential for treating several neurological diseases, including Huntington’s disease (HD). However, exogenous BDNF or monoclonal antibody agonists as therapeutic agents have potential limitations for therapeutic use. To overcome this, two BDNF small molecule mimetics, LM22A-4 and 7,8- dihydroxyflavone (7,8-DHF), with specific affinity for the TrkB receptor, were developed and are potential candidates for treating HD. This study investigated whether LM22A-4 or 7,8-DHF could support the generation of MSNs from directly reprogrammed human-induced striatal precursor cells (hiSNPs) as effectively as BDNF. Briefly, human dermal fibroblasts were reprogrammed into hiSNPs by transfecting with lipid nanoparticle SOX2 and PAX6 mRNA. During differentiation, cells were treated with either 1nM BDNF, LM22A-4 (5µM, 10µM and 20µM) or 7,8-DHF (5µM, 10µM and 20µM), then fixed for immunocytochemistry and Sholl analysis or collected for ELISA. Treatment of hiSNPs with either LM22A-4 or 7,8-DHF generated the same number of DARPP32+ MSNs as quantified following treatment with BDNF. We also observed no difference in neurite length or branch number of MSNs following LM22A-4 or 7,8-DHF treatment compared to BDNF. Phosphorylation of the TrkB receptor following LM22A-4 or 7,8-DHF treatment was equivalent to that produced by BDNF as determined by ELISA analysis. This research demonstrates that small molecule TrkB agonists can promote the generation of MSNs from hiSNPs comparable to BDNF, indicating these compounds have the potential for the treatment of HD.