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early 13c., "notably large, bulky, or strong" (a sense now obsolete), from Old English mægen- "power, strength, force," used in compounds (such as mægensibb "great love," mægenbyrðen "heavy burden;" see main (n.)), probably also in part from or influenced by cognate Old Norse megenn (adj.) "strong, powerful, mighty."
Sense of "chief, principal, prime" is from c. 1400. That of "principal or chief in size or extent" is from 1590s. Main chance "opportunity of enriching oneself" is by 1570s, from the game of hazard. Main course in the meal sense attested from 1829. Main man "favorite male friend; hero" is by 1967, African-American vernacular.
Meaning "sustaining parts of a structure fitted together" is from c. 1400. Meaning "enclosing border" of any kind is from c. 1600; specifically "border or case for a picture or pane of glass" from 1660s. The meaning "human body" is from 1590s. Of bicycles, from 1871; of motor cars, from 1900. Meaning "separate picture in a series from a film" is from 1916. From 1660s in the meaning "particular state" (as in Frame of mind, 1711). Frame of reference is 1897, from mechanics and graphing; the figurative sense is attested from 1924.