Brown macroalgae, so called seaweed, has shown promising potential to produce biofuel and biobased chemicals. However, a single-product biorefinery producing biofuel from seaweed at an industrial scale has many economic obstacles, hindering its commercialization. In the present contribution, a model-based process analysis was performed in which (1) the main economic barriers of an only-fuel approach were studied extensively, (2) an innovative biorefinery approach was applied to remove the economic impediments and pave the way to the commercialization of a seaweed-based biorefinery. Nizimuddinia zanardini, a natural and widely available brown macroalga in Iran, was chosen as the plant's feedstock. In the only-fuel approach, the seaweed was used to produce fuel ethanol and electricity exclusively. In the biorefinery approach, an integrated process was applied to produce fuel ethanol, electricity, and high-value chemicals, i.e., mannitol, alginate, and protein. Simulations were conducted by Aspen Plus®, and the results were employed to perform an economic analysis. Considering the internal rate of return of 20% for the plant location, the profitability indices of both process frameworks were calculated. Based on the profitability indices, the only-fuel approach was economically unviable, mainly due to the low conversion rate of ethanol from seaweed carbohydrates. On the other hand, the biorefinery approach was cost-effective, having produced highly valuable chemicals. Therefore, it is much more lucrative to produce high-value chemicals besides biofuel than to exclusively produce biofuel from seaweed feedstock. The maximum allowable dry seaweed price (MDSP) was −64 and 374 US$ per ton of dry seaweed for the only-fuel and biorefinery approaches, respectively. MDSP of the biorefinery approach can be used to set a benchmark price for future studies on seaweed cultivation.