The Brine Shrimp Lethality Assay (BSLA) is a rapid and economical assay that has been used to screen plant extracts for potential anti-tumor compounds. The objective of this study was to screen Mid-Michigan plant extracts for activity in the BSLA to identify candidates for further pharmacological study. Based on the knowledge that many plants found in the region have been used in Native American traditional medicine for a variety of conditions, including cancer, we hypothesized that some plants would demonstrate activity in the BSLA. In addition, we aimed to determine any difference in sensitivity between the traditional test tube format and the more recently developed microwell format of the assay. After a preliminary screening of 38 plant extracts, eight extracts were active in the BSLA, including Achillea millefolium, Nepeta cataria, and Podophyllum peltatum. Both A. millefolium and N. cataria have been used as cold remedies in Native American traditional medicine, while P. peltatum derivatives etoposide and teniposide are current anti-tumor drugs. We also demonstrated that the sensitivity of the assay is dependent on the assay format. Percent lethality was higher in the 96-well plate format when compared to the 5 mL glass test tube format. These results suggest that several plants from the Mid-Michigan region may be worthy of further investigation to characterize their biological activity as it relates to potential anti-cancer properties. Furthermore, we suggest that researchers use the 96-well BSLA format to increase sensitivity and inter-laboratory consistency of the assay.