"Context," or the sentence and environment in which the word is being used, can be helpful in determining what it means.
An example: "The peaceful countryside at sunset was very bucolic." Even if you don't know what "bucolic" means, you can infer a lot from the way it is used. If bucolic describes a peaceful countryside, it likely has something to do with quietness, loveliness or peacefulness. If you don't have time to look up the word, the context can tell you enough at least to keep reading.
Sometimes a printed word only looks unfamiliar, but if you were to hear it said aloud, you'd recognize it.
For example, if the car a character drives is a "jalopy," you might find yourself skimming all the foreign makes and models for a "JAY-luh-pee." But when you hear it spoken, "Ja-LOP-ee," you might remember the term describes an old-fashioned, rundown car.
Sound out unfamiliar words. Experiment with different emphasis and vowel sounds, and listen to how the word sounds on your tongue. Perhaps the word will be revealed to you orally.
Many English words are formed by tacking prefixes at the beginning and suffixes at the end of simple words. Sometimes dissecting a word---looking for familiar structures inside it---can help you decode it.
Take a word such as "hyperthyroidism." Break the word into its parts. "Hyper" might be a word you've heard to describe an overactive kid. Thyroid, the root word, is a functioning part of the body. 'Ism' is a suffix you're familiar with in many other words, such as activism, feminism or magnetism. In all these examples the "ism" indicates a state of being or condition. So if you put the three parts together, you get "Overactive" "Thyroid" "Condition." And you've just defined a difficult word by examining the familiar elements.